OA13017A

OA13017A - Diazepinoindole derivatives as kinase inhibitors.

Info

Publication number: OA13017A
Application number: OA1200500197A
Authority: OA
Inventors: Suzanne BENEDICT; Michael John Bennett; Sacha Ninkovic; Eugene Yuanjin Rui; Min Teng; Yong Wang; Fen Wang; Zhu Jinjiang
Original assignee: Pfizer
Priority date: 2003-01-09
Filing date: 2004-01-05
Publication date: 2006-11-10
Also published as: IS7884A; ECSP055911A; KR100697746B1; UA80733C2; JP3990718B2; AP2048A; CN1759118A; ATE404564T1; US6967198B2; AP2005003353A0; AU2004203977B2; NZ540638A; EP1585749A1; KR20050092397A; DK1585749T3; RS20050522A; NO20053775D0; PL378372A1; EA200500893A1; ES2309484T3

Abstract

The present invention relates to the combined use of a compound of formula (I) wherein A, X, Y, Z, R 2 , R 3 and R 4 are as defined in the description, and an anti-neoplastic agent, for the treatment of neoplasms.

Description

013017 1

TRICYCLIC COMPOUNDS PROTEIN KINASE INHIBITORS FOR ENHANCING THEEFFICACY OF ANTI-NEOPLASTIC AGENTS AND RADIATION THERAPY

Field of The Invention

This invention relates to novel tricyclic compounds of formula I that inhibit proteinkinases, preferably CHK-1. The invention further relates to pharmaceutical compositionscontaining such compounds, and to methods for the treatment of a condition which can be treatedby the inhibition of protein kinases, preferably CHK-1, in a mammal by administering effectiveamounts of such compounds in conjunction with an anti-neoplastic agent, a radiation therapy, oras a single agent.

Backaround of The Invention A eukaryotic cell cycle has a carefully regulated progression of phases: initial gap (G-O,DNA synthesis (S), secondary gap (G2), and mitosis (M). Gi, S and G2 are known as interphase.In Gi, the cell, whose biosynthetic pathways were slowed during mitosis, résumés a high rate ofRNA and protein .biosynthesis. The S phase begins when DNA synthesis starts and ends whenthe DNA content of the nucléus has been repiicated. The cell then enters G2 where again RNAand protein biosynthesis occur. Following G2, the cell enters M phase that begins with nucleardivision and ends with the complété division of the cytopiasm into two daughter cells. This marksthe beginning of interphase for the new cells. Non-dividing cells exist at Go, a time followingmitosis and before DNA synthesis.

Checkpoint enzymes, such as the serine/threonine protein kinase called checkpointkinase 1 (CHK-1 or p56CHK-1), are responsible for maintaining the order and fidelity of events inthe cell cycle. CHK-1 transduces signais from the DNA damage sensory complex to inhibitactivation of Cdc2-cyclin B complex which promotes mitotic entry (Science, 277, 1501-1505(1997); Science, 277, 1497-1501 ((1997)). In eukaryotes, Cdc2 is known as Cdk1 (cyclin-dependent kinase 1). CHK-1 régulâtes Cdc25, a dual specificity phosphatase that activâtes Cdc2.Thus, CHK-1 serves as the direct link between the G2 checkpoint and the négative régulation ofCdc2.

Healthy cells hâve both the G-, and G2 checkpoints and their associated repair processesto ensure viability after treatment of DNA damage (chemotherapy and/or radiation). Cancer cells,however, rely exclusively on the G2 checkpoint and its associated repair processes in order toremain viable and to continue réplication. Abrogation of the G2 checkpoint would leave cancercells with no means to delay progression into mitosis following DNA damage. Inactivation ofCHK-1 has been shown to abrogate G2 arrest induced by DNA damage inflicted by eitheranticancer agents or endogenous DNA damage. In addition, inactivation of CHK-1 results inpreferential kiiling of the resulting DNA damaged, checkpoint defective cells (Ce//, 91, 865-867(1997); Science, 277, 1450-1451 (1997); Nature, 363, 368-371 (1993); Molec. Biol. Cell, 5, 147-160 (1994)). Therefore there is a need for small molécule inhibitors of CHK-1 to preferentially 013017 2 abrogate the G2 checkpoint over G-, and to effectively remove the only checkpoint control foundin many types of cancers. When administered during the course of a DNA damaging event, suchas chemotherapy employing anti-neoplastic agents, radiation therapy, immunothérapies andantiangiogenic thérapies, a CHK-1 inhibitor can sensitize cancer celis thereby triggering damage-mediated apoptosis. Therefore there is a need for a combination therapy involving CHK-1 inhibitorin the course of a DNA damaging event.

Since protein kinases are ubiquitous and interrelated, sélective modulation of a singlekinase, such as CHK-1, or family of kinases may not resuit in an effective therapeutic treatment.There is therefore a need for small molécule inhibitors to influence one or more targeted proteinkinases whose inhibition, taken as a whole, would produce the desired therapeutic treatment.Although kinase selectivity and its relation to generalized toxicity are important, therapeuticefficacy may rely on the inhibition of more than one protein kinase. Chemical core structures thatcan be suitably appended to interact selectively and potently with targeted protein kinasesrepresent a valuable tool for drug discovery and scientific research. Therefore there is a need forsuch a core structure as an inhibitor of one or more protein kinases. Whether administered as asingle agent or as co-therapy, the protein kinase inhibitors, such as CHK-1 inihibitors, of theprésent invention couid prove bénéficiai in the treatment of a number of human diseases, such ascancer.

Certain CHK-1 inhibitors hâve been proposed for cancer therapy (see Sanchez, Y. étal.(1997) Science 277: 1497-1501 and Flaggs, G. et al. (1997) Current Biology 7:977-986; U.S.Patent Nos. 6,413,755, 6,383,744, and 6,211,164; and International Publication Nos. WO01/16306, WO 01/21771, WO 00/16781, and WO 02/070494).

SUMMARY OF THE INVENTION

An object of the invention is to provide compounds that inhibit the activity of one or moreprotein kinases, such as CHK-1.

In a general aspect, the invention relates to a protein kinase inhibitor, preferably CHK-1inhibitor, tricyclic compounds of the Formula I:

wherein: X is =0 or =S; A is =CR1- or =N-; 013017

The group -Y-Z- has the formula -O-CH2- or -N=CH-; R1 is: (a) (C,-C8)alkyl; (b) -C(=O)-R5; 5 (c) -C(=O)-NR6R7; or (d) R35, or R36, (C2-C8)alkenyl, or (C2-C8)alkynyl {wherein each of said (C2-C8)alkenyl or(C2-C8)alkynyl is unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of F, Cl, OH, -NH2, R40, and R42}; R2 is 10 (a) H, OH, or (CrC8)alkyl; (b) -C(=O)-R8; (c) -(C=S)-R9 or -(C=S)-NR10R11; or (d) R38orR39; R3 is 15 (a) (CrC8)alkyl; (b) -C(=O)-R12; (c) -C(=O)-NR13R14; (d) -NR15-C(=O)-R16; (e) -NR17-SO2R18; 20 (f) -NR19-SOn-NR2DR21 {wherein n is 1 or 2}; (g) -NR22-(C=S)-R23 or -NR22-{C=S)-NR23R24; (h) R36, (C2-C8)alkenyl, or (C2-C8)alkynyl {wherein each of said R3 (C2-CB)alkenyl or(C2-CB)alkynyl is unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of -(C=O)-O-(Ci-CB)alkyl, -O-(C=O)-(C1-C8)alkyl, -(C=O)-(Ci-C8)alkyl, 25 R40, R41, and R42}; (i) R37, -NH2, -NH((C2-C8)aikenyl), -NH((C2-C8)alkynyl), -N((Ci-C8)alkyl)((C2-C8)alkenyl), or-N{(Ci-C8)alkyl)({C2-CB)alkynyl) {wherein each of said R26 (C2-Cs)alkenyl or (C2-C8)alkynyl isunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of R40, R41, and R42}; or 30 0) R38; R4 is selected from the group consisting of H, F, Br, Ci, and (Ci-CB)alkyl; R5 is selected from the group consisting of H, (Ci-C8)alkyi, (C1-C8)alkyl-O-, and R36;

Each R6 and R7 are independently selected from the group consisting of H, (Ci-CB)alkyl, and R36; 35 R8 is selected from the group consisting of (CrC8)alkyl, (C2-C8)alkenyl, (C2-C8)aikynyl, -NH2, R36, and R37; 013017

Each of R9, R10 and R11 are independently selected from the group consisting of H,(CrCeJalkyl, and R36; R12 is selected from the group consisting of H, OH, (CrC8)alkyl, (Ci-C8)alkyl-O-, and R3S; R13 is H or (CrC8)alkyl; R14 is selected from the group consisting of H, (CrC8)alkyl, -CH2-(C=O)-O-(C1-C8)alkyl, and R36; R15 is H or (CrCelalkyl; R16 is selected from the group consisting of H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,-NH2, R35, and R37; wherein each of said R15 and R16 (C2-C8)alkenyl or (C2-C8)alkynyl is unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of R40,R41, and R42; R17 is selected from the group consisting of H, (Ci-C8)alkyl, and R3S; R18is (Ci-Ce)alkyl or R36; R19, R20, and R21 are independently selected from the group consisting of H, (CrC^alkyl, and R36; R22, R23 and R24 are independently selected from the group consisting of H, (Ci-C8)alkyl, and R36; R25 is H or (Ci-C8)alkyl; R26 is selected from the group consisting of -C(=O)-O-C(CH3)3, (C^CeJalkyl,(C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, and (C1-C10)heteroaryl; or R25 and R26 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; R27 is selected from the group consisting of (CrCeJalkyl, (C3-C1o)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, and (CrC^Jheteroaryl; R28 is selected from the group consisting of (CrC8)alkyl, (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, and (Ci-C1D)heteroaryl; R29 is H or (CrC8)alkyl; R30 is (CrC8)alkyl, (C3-C1o)cycloalkyl, (C2-C10)heterocyclyl, (C5-C10)aryl, or(Ci-Cio)heteroaryl; or R29 and R30 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; R31 is H or (CrC8)alkyl; R32 is independently selected from the group consisting of (Ci-C8)alkyl, (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (CrC10)heteroaryl; or R31 and R32 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; 013017 R33 is (CrCe)alkyl, (C3-C10)cycloalkyl, {C2-C10)heterocyclyl, (C6-Ci0)aryl, or (CrCio)heteroaryl; R34 is (C1-C8)alkyl, (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-Cw)aryl, or (CrCio)heteroaryl;

Each R35 is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH,NO2, -NH2i -NH-C(=O)-O-C(CH3)3, and CF3;

Each R36 is independently selected from the group consisting of (C3-C1D)cycloalkyl,(C2-Cio)heterocyclyl, (C6-C10)aiyl, and (CrC10)heteroaryl;

Each R37 is independently selected from the group consisting of: (a) -NR2SR26; and (b) R27-O-; R38 js R28_gon-; wherein n is 0,1, or 2 when -SOn- is bonded to R28 via an R28 carbonatom, or wherein n is 1 or 2 when -SOn- is bonded to R28 via an R28 ring nitrogen atom; R39 is R29R30N-SOn-; wherein n is 1 or 2; wherein each of said (CrCelalkyl, wherever it occurs in any of said R1(a)-(d), Rz(a)-(d),R3(a)-(j), R4, R37, R38, or R39, is unsubstituted or substituted with one to four substituentsindependently selected from the group consisting of (C2-C8)alkenyl, R40, R41, and R42; wherein each of said (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-Ci0)aryl, or(CrCio)heteroaryl, wherever it occurs in said R38, R37, R38, or R39, is independently unsubstitutedor substituted with one to four substituents independently selected from R40; R40is selected from the group consisting of (CrCeJalkyl, R41, R42, and R43;

Each R41 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NO2,-NH2, -NH-C(=O)-O-C(CH3)3, COOH, -C(=O)(C1-C8)alkyl, -C(=O)-O-{Ci-C8)alkyl, -NH-SO2-(Ci-C8)alkyl, -NH-SO2-(C6-C10)aryl, and CF3;

Each R42 is independently selected from the group consisting of (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (Ci-C10)heteroaryl;

Each R43 is independently selected from the group consisting of: (a) -NR31R3Z; (b) R33-O-;and (c) R^-SOn-; wherein n is 0,1, or 2 when -SOn- is bonded to R34 via an R34 carbon atom,or wherein n is 1 or 2 when -SOn- is bonded to R34 via an R34 ring nitrogen atom; wherein each of said (Ci-CB)alkyl, wherever it occurs in any of R40 is independentlyunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of R44 and R45; wherein each of said (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (Cs-Ci0)aryl, or(CrCio)heteroaryl, wherever it occurs in any of said R42 or R43, is independently unsubstituted or 013017 substituted with one to four substituents independently selected from the group consisting of R47selected from the group consisting of (CrCB)alkyl, R44, and R45;

Each R44 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NO2,-NH2, -CF3, -C(=NH)-NH2i -C(=NH)-NH-OH, -C(=NH)-NH-O-(C,-C8)alkyl, -(C=O)-O-(C1-C8)alkyl,-0-(0=0)-(0,-08)3^1, -(C=O)-(C1-C8)alkyl, -(C=O)-NH2, -(C=O)-NH(C,-C8)alkyl, -(C=O)-N<l(C1-Ce)alkyl]2, -NH-(C=O)-(C,-C8)alkyl, R37, and R38;

Each R48 is independently selected from the group consisting of (C3-Ci0)cycloalkyl,(C2-C,0)heterocyclyl, (C6-C10)aryl, and (C1-C10)heteroaryl; wherein each of said (C-,-Ce)alkyl wherever it occurs in any of said R44 or R45 isindependently unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of R46 and R47; wherein each of said (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, or(0,-C 10)heteroaryl, wherever it occurs in any of said R43 or R44 is independently unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of(C,-C8)alkyl, R46and R47;

Each R46is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NO2,-C(=NH)-NH2, -C(=NH)-NH-OH, -C(=NH)-NH-O-(C,-CB)alkyl, -(C=O)-O-(Ci-CB)alkyl,-O-(C=O)-(C,-C8)alkyl, -(C=O)-(C1-C8)alkyl, -(C=0)-NH2, -(C=O)-NH(C1-O8)alkyl, -(C=O)-N<[(C,-CB)alkyl]2, -NH-(C=O)-(C,-C8)alkyl, -C(=NH)-NH2, -C(=NH)-NH-OH, -C(=NH)-NH-O-(C1-C8)alkyl, -(C=O)-O-(C,-C8)alkyl, -O-(C=O)-(C,-C8)alkyl. -(C=O)-(Ci-C8)alkyl,-(C=O)-NHZ, -(C=O)-NH(C,-Cs)alkyl, -(C=O)-N>[(C,-CB)alkyl]2, -NH-(C=O)-(Ci-C8)alkyl, R37, andR38; and

Each R47 is independently selected from the group consisting of (C3-C10)cycloalkyl;(C2-C10)heterocyclyl, (C6-C,o)aryl, and (C,-C1t))heteroaryl; or a pharmaceutically acceptable sait thereof.

The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceuticallyactive métabolites, and pharmaceutically acceptable salts of the compounds of Formula I.Pharmaceutically acceptable salts of such active métabolites are also provided. Advantageousmethods of making the compounds of the Formula I are also described.

The compounds of this invention include ail stereoisomers (e.g., cis and trans isomers) andail optical isomers of compounds of the Formula l (e.g., R and S enantiomers), as well as racemic,diastereomeric and other mixtures of such isomers.

The compounds of the invention may also exist in different tautomeric forms. This inventionrelates to al! tautomers of Formula I.

The compounds of this invention may contain olefin-like double bonds. When such bondsare présent, the compounds of the invention exist as cis and trans configurations and as mixturesthereof. 013017 7

In one embodiment, the invention relates to compounds of the Formula I wherein R3 is(Ci-C8)alkyl substituted with one to four substituents independently selected from the groupconsisting of F, OH, -NH2, (CrC8)alkyl-NH-, (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl,and (Cs-Cio)heteroaryl.

In another embodiment, the invention relates to compounds of the Formula I wherein R3is selected from the group consisting of (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C6)cycloalkyl, (C2-C10)heterocyclyl, phenyl, and (CrCi0)heteroaryl; wherein each of said (C2-C8)alkenyl or (C2-C8)alkynyl is unsubstituted or substituted with one to three substituents independently selectedfrom the group consisting of F, OH, -NH2, (C-i-CsJalkyl-NH-, [{C1-C8)alkyl]2>N-, (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C,o)aiyl, and (C1-C10)heteroaryl; and wherein each of said(C3-Cs)cycloalkyl, (C2-C10)heterocyclyl, phenyl, or (C^C^Jheteroaryl is unsubstituted or substitutedwith one to four substituents independently selected from the group consisting of (CrC8)alkyl, F,OH, -NH2, (C,-C8)alkyl-NH-, [(C1-C8)alkyl]2>N-, (C3-Ci0)cycloalkyl, (C2-C10)heterocyclyl, (Ce-C10)aryl, and (CrC^Jhetèroaryl.

In a preferred embodiment, the invention relates to compounds of the Formula I whereinr3 js -C(=O)-NR13R14 {wherein R13 is H or (Ci-C8)alkyl}, wherein said R13 (CrC^alkyl isunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of F, OH, -NH2, R41, and R42; wherein each of said R3S is unsubstituted or substitutedwith one or two substituents independently selected from the group consisting of (C6-C10)aryl,(CrCio)heteroaryl, (C2-Ci0)heterocyclyl, (C,-C8)alkyl-NH-, and [(CrCeJalkyO^N-; and whereineach of said (Ce-Ciolaryl substituent is unsubstituted or substituted with one to three substituentsindependently selected from the group consisting of (CrCB)alkyl, F, Cl, -CF3, and OH.

In another embodiment, the invention relates to compounds of the Formula I wherein R15is (Ci-Celalkyl unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of OH, CN, -NH2, (Ci-C8)alkyl-NH-, [(CrC8)alkyl]2>N-,[(C1-C8)alkyl][(C3-C10)cycloalkyl]>N-, (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, and(CrC10)heteroaryl; wherein said (Ce-C10)aryl substituent is unsubstituted or substituted with one tofour substituents independently selected from the group consisting of (Ci-C8)alkyl, F, Cl, Br, CN,OH, and CF3; and wherein said (C2-C10)heterocyclyl substituent is unsubstituted or substitutedwith one or two substituents independently selected from the group consisting of (C1-C8)alkyl,-(C=O)-(Ci-C8)alkyl, -(C=O)-O-(CrC8)alkyI, -S-fCrCgJalkyl, F, Br, OH, and CF3.

In another embodiment, the invention relates to compounds of the Formula I wherein R3is -NR15-C(=O)-R16; wherein R16 is (C2-C8)alkenyl unsubstituted or substituted with one to foursubstituents independently selected from the group consisting of (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (CrC1D)heteroaryl; wherein said (C6-C10)aryl substituent isunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of (C1-C8)alkyl, F, Cl, Br, CN, OH, and CF3; and wherein said (C2-C10)heterocyclyl 013017 substituent is unsubstituted or substituted with one or two substituents independently selectedfrom the group consisting of (Ci-C8)alkyl, -(C=O)-(CrC8)alkyl, -(C=O)-O-(CrC8)alkyl,-S-(Ci-C8)alkyl, F, Br, OH, and CF3.

In a preferred embodiment, the invention relates to compounds of the Formula I whereinR3 is -NR1S-C(=O)-R16; wherein R16 is (C1-C10)heteroaryl unsubstituted or substituted with one ortwo substituents independently selected from the group consisting of (Ci-C8)alkyl, -(C=O)-(Ci-C8)alkyl, -S-(CrC8)alkyl, F, Cl, CN, OH, and CF3. More preferably the R1® (Ci-C10)heteroarylis pyridinyl.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein R3 is -NR15-C(=O)-R16; wherein R16 is (C3-Ci0)cycloalkyl unsubstituted or substituted withone or two substituents independently selected from the group consisting of (Ci-C8)alkyl, F, Cl,CN, OH, NH2, CF3, (C2-C10)heterocyclyl, (C8-C10)aryl, and (CrC10)heteroaryl; wherein said (C6-C10)aryl substituent is unsubstituted or substituted with one to four substituents Independentlyselected from the group consisting of (Ci-C8)alkyl, F, Cl, Br, CN, OH, and CF3; and wherein said(C2-C10)heterocyclyl substituent is unsubstituted or substituted with one or two substituentsindependently selected from the group consisting of (CrC8)alkyl, -(C=O)-(C1-C8)alkyl,-(C=O)-O-(CrC8)alkyl, -S-fCrCeJalkyl, F, Br, OH, and CF3. More preferably said R16(C3-Cio)cycioalkyl is selected from the group consisting of cyclopropyl and cyclohexyl. Morepreferably said (C6-C10)aryl substituents is unsubstituted.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein R3 is -NR1S-C(=O)-R16; wherein R16 is (C2-Ci0)heterocyclyl unsubstituted or substitutedwith one to four substituents independently selected from the group consisting of (CrCsJalkyl,-(C=O)-(CrC8)alkyl, -(C=O)-O-(CrCB)alkyl, F, Cl, CN, OH, and CF3. More preferably said R16(C2-C10)heterocyclyl is selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl,pyrrolidinonyl, thiadiazolyl, tetrahydroisoquinolinyl, tetrahydronaphthalenyl, and indanyl.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein R3 is -NR1S-C(=O)-R16; wherein R16 is phenyl unsubstituted or substituted with one tothree substituents independently selected from the group consisting of (CrCe)alkyl, (CrC8)alkyl-O-, F, Cl, Br, CN, OH, and CF3.

In another embodiment, the invention relates to compounds of the Formula I wherein R1is (CrCelalkyl substituted with one to two substituents independently selected from the groupconsisting of F, Cl, -OH, -NH2, (Ci-C8)alkyl-NH-, t(C1-CB)alkyl]2>N-, and (Ci-C8)alkyl-O-; whereineach of said (Ci-C8)alkyl substituent, wherever it occurs, is independently unsubstituted orsubstituted with one to three substituents independently selected from the group consisting of -NH2, (C1-C8)alkyl-NH-, [(C1-C8)alkyl]2>N-, -O-(C=O)-(CrCB)alkyl, (C2-C10)heterocyclyl, (C6-C10)aryl,and (CrC10)heteroaryl. 013017

In another embodiment, the invention relates to compounds of the Formula I wherein R1is unsubstituted (CrC8)alkyl; such as methyl or ethyl.

In another embodiment, the invention relates to compounds of the Formula I wherein R1is (C2-CB)alkenyl or (C2-C8)alkynyl; wherein each of said (C2-C8)alkenyl or (C2-C8)alkynyl isunsubstituted or substituted with one to two substituents independently selected from the groupconsisting of -NH2, (CrC8)alkyl-NH-, [(C,-C8)alkyl]2>N-, (C2-C10)heterocyclyl, and(Ci-C10)heteraaryl; wherein each of said (CrC8)alkyl substituent, wherever it occurs, isindependently unsubstituted or substituted with one to three substituents independently selectedfrom the group consisting of -NH2l (CrC8)alkyI-NH-, [(CrC8)alkyl]2>N-, -0-(0=0)-(0,-C8)alkyl,(C2-Cio)heterocyclyl, (Cs-C^aryl, and (C^C^heteroaryl.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein R1 is R36 selected from the group consisting of H, Cl, and Br.

In another embodiment, the invention relates to compounds of the Formula I wherein R1is selected from the group consisting of (C3-C6)cÿcloalkyl, (C2-C10)heterocyclyl, phenyl, and(C,-C 10)heteroaryl; wherein each of said (C2-C10)heterocyclyl, phenyl, or (C,-C10)heteroaryl isunsubstituted or substituted with one to three substituents independently selected from the groupconsisting of (CrC8)alkyl, F, Cl, -NH2, -OH, (Ci-C8)alkyl-NH-, and f(C1-C8)alkyl]2>N-; wherein eachof said (Ci-C8)alkyl substituent, wherever it occurs, is unsubstituted or substituted with one tothree substituents selected from -NH2, (CrC8)alkyl-NH-, [(C1-C8)alkyl]2>N-, -O-(C=O)-(CrC8)alkyl,(C2-Cio)heterocyclyl, (C6-C10)aryl, and (CrC^heteroaryl. Within this embodiment, preferably R1 isphenyl, tetrahydropyridinyl, piperidinyf or pyridinyl.

In another embodiment, the invention relates to compounds of the Formula I wherein R1is _c(=O)-R5, and R5 is (CrCaJalkyl-O- or (C2-Ci0)heterocyclyl, such as morpholinyl; wherein saidR5 (C2-C10)heterocyclyl is unsubstituted or substituted with (CrCelalkyl, such as methyl or ethyl.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein R1 is -C(=O)-NR6R7; wherein each of said R6 and R7 are independently H or (CrCe)alkyl;and wherein each of said R6 and R7 (CrCsJalkyl are unsubstituted or substituted with one to threesubstituents independently selected from the group consisting of OH, -NH2, (CrC8)alkyl-NH-,[(CrCeJalkylJ^N-, (C2-C10)heterocyclyl, and (CrC10)heteroaryl.

In another preferred embodiment, the invention relates to compounds of the Formula lwherein R2 is H or (Ci-C8)alkyl unsubstituted or substituted with one to four substituentsindependently selected from the group consisting of OH, -NH2, (CrC^alkyl-NH-, [(C1-C8)alkyl]2>N-, (C2-C10)heterocyclyl, and (C,-C10)heteroaryl.

In another embodiment, the invention relates to compounds of the Formula I wherein A is =N-,

In another embodiment, the invention relates to compounds of the Formula I wherein R2is -C(=0)-R8. wherein R8 is selected from the group consisting of (CrC8)alkyl, (C2-C8)alkenyl, (C2- 013017 10 CB)alkynyl, -NH2, and R37 selected from the group consisting of (CrCsIalkyl-NH-,[(Ci-Ce)alkyl]2>N-, and (CrC0)alkyl-O-; wherein each of said R8 and R37 (Ci-CB)akyl, wherever itoccurs, is independently unsubstituted or substituted with one to four substituants independentlyselected from R40 selected from the group consisting of F, OH, -NH2, (C3-C10)cycloalkyl,(C2-C1D)heterocyclyl, (C6-C,0)aryI, (CrCio)heteroaryl; (CrCfOalkyl-NH- and [(CrC8)alkyl]2>N-; wherein each of said R40 (CrC^alkyl, wherever it occurs, is independently unsubstitutedor substituted with one to four substituents independently selected from R44 independentlyselected from the group consisting of OH, -NH2, (C-i-CeJalkyl-NH-, [(CrC8)alkyl]2>N-, and(C3-C10)cycloalkyl-NH-; wherein each of said each of said R40 (C3-C10)cycloalkyl, (C2-C10)heterocyclyl,(C6-C10)aryl, or (CrC10)heteroaryl, wherever it occurs, is independently unsubstituted orsubstituted with one to four substituents independently selected from R47 selected from the groupconsisting of (C^Celalkyl, OH, -NH2, (C,-C8)alkyl-NH-, [(C1-Cs)alkyl]2>N-, and (C3-C10)cycloalkyl-NH-; and wherein each of said R47 (Ci-C8)alkyl, wherever it occurs, is independently unsubstitutedor substituted with one to four substituents independently selected from the group consisting ofOH, -NH2, (C^Celalkyl-NH-, [(C1-CB)alkyl]2>N-, and (C3-C10)cycloalkyl-NH.

In another embodiment, the invention relates to compounds of the Formula I wherein R2is -C(=O)-R8, wherein R8 is selected from the group consisting of (C3-C5)cycloalkyl, (C2-C10)heterocyclyl, phenyl, or (C1-C10)heteroaryl; wherein each of said R8 (C3-CB)cycloalkyl, (C^CiD)heterocyclyl, phenyl, or (CrCwJheteroaryl is unsubstituted or substituted with one to foursubstituents independently selected from R40 selected from the group consisting of (CrCeJalkyl, F,OH, -NH2, (C1-Ce)alkyl-NH-, [(C1-CB)alkyl]2>N-, (C3-C10)cycloalkyl, (C^-C^heterocyclyl, (C8-Cio)aryl, and (C-i-C^lheteroaryl; wherein each of said R40 (CrCB)alkyl, wherever it occurs, isindependently unsubstituted or substituted with one to four substituents independently selectedfrom R44 independently selected from the group consisting OH, -NH2, (C1-Ce)alkyl-NH-,[(Ci-CB)alkyl]2>N-, and (C3-C10)cycloalkyl-NH-; wherein each of said R40 (C3-C10)cycloalkyl,(C2-Cio)heterocyclyl, (C6-C10)aryl, or (CrCi0)heteroaryl is unsubstituted or substituted with one tofour substituents independently selected from R47 selected from the group consisting of (CrC8)alkyl, OH, -NH2, (C-|-Ca)alkyl-NH-, [(C1-C8)alkyl]2>N-, and (C3-Ci0)cycloalkyl-NH-; wherein eachof said R47 (CpCsIalkyl, wherever it occurs, is unsubstituted or substituted with one to foursubstituents independently selected from the group consisting of OH, -NH2, (Ci-Cg)alkyl-NH-,[(Ci-C8)alkyl]2>N-, and (C3-C10)cycloalkyl-NH.

In another embodiment, the invention relates to compounds of the Formula I wherein saidR3 is on any one of position 7, 8, or 9 of said compound of the formula I. Preferably, the inventionrelates to compounds of the Formula I wherein said R3 is on position 8 of said compound of theformula I. 013017 11

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein said R4 is on position 7 of said compound of the formula I. More preferably, said R3 is onposition 8 of said compound of the formula I and said R4 is on position 7 of said compound of theformula I.

In another embodiment, the invention relates to compounds of the Formula I wherein saidR4 is Cl or Br on position 7 of said compound of the formula I. in another preferred embodiment, the invention relates to compounds of the Formula Iwherein said R4 is H on position 7 of said compound of the formula I.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein X is O.

In another preferred embodiment, the invention relates to compounds of the Formula Iwherein the group -Y-Z- has the formula -N=CH-,

Preferably the invention relates to compounds of the Formula I selected from the group/V-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdlindol-8-yl}-2-phenyl-acetamide; 2- Cyclohexyl-/V-(6-oxo-2-phenyl-5,6-dihydro-1/7-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide; /V-(6-Oxo-2-phenyl-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-phenyl- butyramide; A/-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-3-phenyl- propionamide; 3- Fluoro-2-methyl-/\/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-ccQindol-8-y!)-benzamide; 2-Fluoro-N-(6-oxo-2-phenyl-5,6-dihydro-1B-[1,2]diazepino[4,5,6-cdJindol-8-yl)-3-trifluoromethyl-benzamide; /V-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-trifluoromethyl- benzamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H- [1,2]diazepino[4,5,6-cd]indol-8-yI)-amide; 2- (3-Chlorophenyl)-/V-(6-oxo-2-pheriyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)acetamide; /V-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdîindol-8-yl)-4-thien-2- ylbutanamide; 1 -Acetyl-W-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)piperidine-4-carboxamide; 3- (2-Methylphenyl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)propanamide; 013017 12 (2S)-2-Amino-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1l2]diazepino[4,5,6-cd]indol-8-yl)-4-phenyl-butyramide compound with trifluoro-acetic acid; (2R)-2-Amino-2-cyclohexyl-/\/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)ethanamide trifluoroacetate; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd|indol-8-yl)-amide; 2-Ethylsulfanyl-W-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4t5,6-cdJindol-8-yl)-nicotinamide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cdlindol-8-yl)-amide; /V-[2-(3-Dimethylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1/7-[1,2]diazepino[4,5,6-cd]indol- 8-yl]-2-fluoro-3-trifluoromethyl-benzamide; 6-Oxo-2-phenyl-A/-(2-phenylcyclopropyl)-5,6-dihydro-1/-/-[1,2]diazepino[4I5,6-cc/]indole-8- carboxamide; /V-[1-(4-Fluorophenyl)ethyl]-6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole- 8-carboxamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid f2-(3-dimethylaminomethyl-phenyl)-5-oxo- 5,6-dihydro-1 H-{ 1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylaminomethyl-phenyl)-6-oxo- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide (hydrochloric sait);

Acetic acid 3-{6-oxo-8-[((1R, 2R)-2-phenyl-cyclopropanecarbonyI)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-2-yl}-benzyl ester; (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/]indol-8-yl]-amide; (2R)-2-Amino-2-cyciohexyl-W-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4l5,6-cd]indol-8-yl)-acetamide (hydrochloric sait); /V.[1-(4-Hydroxyphenyl)ethylJ-6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indole-8-carboxamide; 2,3-Difluoro-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indoi-8-yl)- benzamide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cc0indol-8-yl)-amide; W-(4-Fluorobenzyl)-6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indole-8-carboxamide; (1R,2R)-2-Phenyl-cyclopropanecarboxyIic acid [2-(3-cyclobutylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide(hydrochloric sait); 013017 13 (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1 -ylmethyl-phenyl)- 5,6-dihydro-1 ,2]diazepino[4,5,6-cd]indol-8-yl]-amide(hydrochloric sait); /V-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-(1,2-irans)-2-[6- (trifluoromethyl)pyridin-3-yl]cyclopropanecarboxamidetrifluoroacetaté; (2R)-2-Amino-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenyl-acetamide (hydrochloric sait); (2R)-2-Amino-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indol-8-yl)-3-phenyl-propionamide(hydrochloric sait); (3E)-4-Phenyl-but-3-enoic acid (6-oxo-2-phenyl-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-cd)indol-8-yl)-amide; 2-lndan-2-yl-/V-(6-oxo-2-phenyl-5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide; (1,2-frans)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cdJindol-8-yl)-amide; (1,2-/rans)-2-Pyridin-3-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd|indol-8-yl)-amide (hydrochloric sait); (1,2-frans)-2-(3-Methoxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepinof4,5,6-cdJindol-8-yl)-amide; 2-lndan-2-yl-(6-oxo-5,6-dihydro-1-(1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide; (2R)-2-Hydroxy-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-(1,2]diazepino[4l5,6-cd3indol-8-yl)-2- phenylethanamide; (1,2-frans)-2-Pyridin-2-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cc(lindol-8-yl)-amide acetic acid; (1,2-frans)-2-(1H-lmidazol-4-yl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide acetic acid; (2R)-Piperidine-2-carboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[ 1,2]diazepino[4,5,6-cd)indol-8-yl)-amide (hydrochloric sait); (2S)- 2-Amino-3-cyano-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[ 1,2]diazepino[4,5,6-cd]indol-8-yl)-propionamide acetic acid; (2R)-2-amino-3-(4-hydroxyphenyl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)propanamide (hydrochloric sait); (1 R,2R)- 6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid methyl ester; (2R)-3-(4-Hydroxypheny])-2-(methyiamino)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cdJÎndol-8-yi)propanamide (hydrochloric sait); (2R)-2-Amino-3-(4-fluorophenyl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1>2]diazepino[4,5,6-cd]indol-8-yI)propanamÎde (hydrochloric sait); 013017 14 (1 R,2R)- 6-Oxo-8-{(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccflindole-2-carboxylic acid methylamide; (1 R,2R)- 6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid {2-hydroxy-ethyl)-amide; (1 R,2R)- 6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-C£/)indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; (2R)-2-Amino-2-(4-hydroxyphenyl)-AZ-(6-oxo-2-phenyl-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cc/]indol-8-yl)ethanamide (hydrochloric sait); (1,2-ira/?s)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1- [1,2Jdiazepino[4,5,6]indol-8-yl)-amide; (1,2-frans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6- dihydro-1 -[1,2]diazepino[4,5,6]indol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cdJindol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-chloro-6-oxo-5,6-dihydro-1/-/- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; ( 1,2-frans)-2-(3-Bromo-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; (1,2-irans)-2-(3-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1- [1.2] diazepino[4,5,6]indol-8-yl)-amide; 2-(3,4-Dihydroisoquinolin-2(1H)-yl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)acetamide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-bromo-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cc/|indol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid I6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)- 5,6-dihydro-1 tf-[1,2]diazepino[4,5,6-cc/]indol-8-yi]-amide (hydrochloric sait); (1 R,2R)-/V-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenylcyclopropanecarboxamide; A/-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1 /7-[1,2]diazepino[4,5,6-cd]indol-8-y!)-(1,2-trans)-2-pyridin-3-yicyclopropanecarboxamide; /V-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-(1,2-trans)-2-pyridin-3-yicyctopropanecarboxamide; (1Rl2R)-/V-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-cc0indol-8-yl)-2- phenylcyclopropanecarboxamide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-prop-1-ynyl)-6-oxo- 5,6-dihydro-1 H-[1,2]diazepinoJ4,5,6-cd]indol-8-yl]-amide; 013017 15 (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid l2-(3-dimethylamino-propyl)-6-oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cc/Jindol-8-yl]-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-propenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-yl]-amide; 5 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6- dihydro-1W-[1,2]diazepina[4,5,6-cd]indol-8-ylJ-amide (hydrochloric sait); (1,2-frans)-2-Pyridin-3-yl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide (dihydrochloric sait); (2R)-2-Amino-2-cyclohexyl-A/-[2-(3-methylamino-prop-1-ynyÎ)-6-oxo-5,6-dihydro-1H-10 [1,2]diazepino[4,5,6-ccdindol-8-yl]-acetamide (dihydrochloric sait); (1,2-ira/?s)-/V-[1-(2-Hydroxyethyl)-6-oxo-5;6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl]- 2-phenylcyclopropanecarboxamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-dimethylaminomethyl-6-oxo-5,6-dihydro-1 /7-[1,2]diazepino[4,5,6-cd]indol-8-y!)-amide; 15 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1-(2-amino-ethyl)-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-morpholin-4-yl-prop-1 -ynyl)-6-oxo- 5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1-yl-prop-1-ynyl)-5,6-20 dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; and (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid I1-(2-amino-ethyl)-2-chloro-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1R,2R)-2-Phenyl-cyciopropanecarboxylic acid (2-(1/7-imidazol-2-yl)-6-oxo-5,6-dihydro-1 H-[î ,2]diazepinoI4,5,6-cd]indol-8-yl]-amide; 25 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-cyano-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cdJindol-8-yl)-amide; and (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(1H-imidazol-2-yl)-6-oxo-5,6-dihydro-1 /7-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; or the pharmaceutically acceptable salts or solvatés thereof. 30 Other preferred compounds are selected from the group consisting of: 3-Fluoro-2-methyl-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-benzamide; 2-Fluoro-W-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5l6-cc(lindol-8-yl)-3- trifluoromethyl-benzamide; 35 /V-(6-Oxo-2-phenyl-5,6-dihydro-1/-i-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-thien-2- ylbutanamide; 013017 16 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyi-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylaminomethyl-phenyl)-6-oxo- 5.6- dihydro-1 H-[1,2]diazepino[4,5,6-cd|indol-8-yl]-amide; 5 Açetic acid 3-{6-oxo-8-[((1R, 2R)-2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cdjindol-2-yl}-benzyl ester; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid f2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[î ,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-/V-(6-oxo-2-pheriyl-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-10 cd]indol-8-yl)-acetamide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H- [l^jdiazepino^.S.e-cdJindol-S-yQ-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-cyclobutylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdlindol-8-yl]-amide; 15 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1-ylmethyl-phenyl)- 5.6- dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; 2-lndan-2-yl-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)- acetamide; (1,2-irans)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-20 1W-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide; (2R)-2-Amino-3-{4-hydroxyphenyl)-/\/-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccWndol-8-yl)propanamide; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbûnyi)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cdIindole-2-carboxylic acid methyl ester; 25 (1 R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid methylamide; (1R,2R)-6-Oxo-8-[(2-phenyl-cycIopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diaze'pino[4,5,6-cd]indole-2-carboxylic acid (2-hydroxy-ethyl)-amide; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H-30 [1,2]diazepino[4,5,6-cd]indole-2-carboxylic acid (2-hydroxy-ethyl)-amide; (2R)-2-Amino-2-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1W- [1.2] dÎazepino[4,5,6-cd]indo!-8-yl)ethanamide; ( 1,2-trans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H-[1,2Jdiazepino[4,5,6-C(ï]indol-8-yl)-amide; 35 (1,2-t/a/7s)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid . (6-oxo-2-phenyl-5,6- dihydro-1-[1,2]diazepino[4,5,6]indol-8-yl)-amide; 013017 17

(1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1 H

[1.2] diazepino[4^6-ccf]indol-8-yl)-arnide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1 H- [1.2] diazepinoI4,5,6-cd]indol-8-yl)-amide; 5 2-(3,4-DÎhydroisoquinolin-2(1/7)-yl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1/V- [1.2] diazepino[4,5,6-cdJindol-8-yl)acetamide; 2-(3,4-Dihydroisoquinolin-2(1H)-yl)-W-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)acetamide; (1R,2R)-2-Phenyl-cyclopropanecarboxyiic acid [6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-10 5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1R,2/?)-/V-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cdlindol-8-yl)-2- phenylcyclopropanecarboxamide; (1 R,2R)-W-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1 H-[ 1,2]diazepino[4,5,6-cdlindol-8-yl)-2-phenylcyclopropanecarboxamide; 15 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-(3-dimethylamino-prop-1-ynyl)-6-oxo- 5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-yl]-amide; , ( 1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-propenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-20 dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-A/-[2-(3-methylamino-prop-1-ynyl)-6-oxo-5)6-dihydro-1/7-[1,2Jdiazepino[4,5,6-cdlindol-8-ylJ-acetamidede; (1R,2R)-2-Phenyi-cyclopropanecarboxylic acid (2-hydroxymethyl-6-oxo-5,6-dihydro-1H-[1,2-ctfldiazepino[4,5,6]indol-8-yl)-amide; 25 (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1 -yl-prop-1 -ynyl)-5,6- dihydro-1 H-[1,2]diazepinoI4,5,6-cd]indoi-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(1H-imidazol-2-yl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indoi-8-yl]-amide,· (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-cyano-6-oxo-5,6-dihydro-1H- 30 [1,2]diazepÎno[4,5,6-cd]indol-8-yl)-amide; and (2R)-2-Amino-2-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cdJindol-8-yl)ethanamide hydrochloride; or the pharmaceutically acceptable salts or solvatés thereof.

Other preferred compounds of formula l are selected from the group consisting of: 35 2-Fluoro-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-(1,2]diazepino[4,5,6-cd]indol-8-yl)-3- trifiuoromethyl-benzamide; 013017 18 A/-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-thien-2- ylbutanamide; (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid {2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cdJindol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6- cd]indol-8-yl)-acetamide(hydrochloride); 6-Oxo-2-phenyl-W-[(1R)-1-phenylethyl]-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-cd]indole-8- carboxamide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; (2R)-2-Hydroxy-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-('l ,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenylethanamide; (1,2-frans)-2-Pyridin-2-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide (acetic acid sait); (1,2-fra/?s)-2-(1 H-lmidazol-4-yl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-yl)-amide (acetic acid sait); (2R)-Piperidine-2-carboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-ccf|indol-8-yl)-amide (hydrochloric sait); (2R)-2-Amino-3-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccQindol-8-yl)propanamide hydrochloride; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino{4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide;

Example 182: (1,2-frans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5l6-dihydro-1-[1.2]diazepino[4,5,6]indol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1 H-[1,2Jdiazepino[4,5,6-cd]indol-8-yl)-amide; (1 R,2R)-/V-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-ccf|indol-8-yl)-2-phenylcyclopropanecarboxamide; and (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1-(2-amino-ethyl)-2-chloro-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; or the pharmaceutically acceptable salts or solvatés thereof.

In another embodiment, the invention also relates to compounds of the Formula I that aresélective for CHK-1 over CHK-2 with selectivity ratio between about 5 folds and about 5000 folds;preferably between about 50 folds and about 1000 folds; and more preferably between about 70folds and about 830 folds. Within this embodiment, the more preferred compounds are selectedfrom the group consisting of: 013017 19 2-FluoroJV-(6-oxo-2-phenyl<6Hjihydro-1H41.2]diazepino[4^6-cc(]inclol-8-yl)-3- trifluoromethyl-benzamide; /V-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-trifluoromethyl- benzamide; 5 /V-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-thien-2- ylbutanamide; /V-[2-(3-Dimethylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-2-fluoro-3-trifluoromethyl-benzamide; (2R)-2-Amino-2-cyclohexyl-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6- 10 cc/]indol-8-yl)-acetamide(hydrochloride); (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H- [1,2]diazepino[4,5,6-cd]indol-8-yl)-amide; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl}-aminol-5,6-dihydro-1H- [1,21diazepino[4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; 15 (2R)-2-Amino-2-(4-hydroxyphenyi)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1,23diazepino(4,5,6-cc/]indol-8-yl)ethanamide hydrochloride; (1,2-frans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1-[1,2]diazepino[4,5,6]indol-8-yl)-amide; and (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1 H- 20 [1,2]diazepino[4,5,6-ccf|indol-8-yi)-amide; or the pharmaceutically acceptable salts or solvatés thereof.

Another object of the invention is to provide a composition for the treatment of neoplasms,and for enhancing the antineoplastic effects of anti-neopiastic agents and therapeutic radiation.

In an embodiment, the invention relates to a composition containing a compound of the 25 Formula I, a pharmaceutically acceptable sait, solvaté, or prodrug thereof and an anti-neoplasticagent as a combined préparation for the sïmultaneous, separate or sequential use in treating aneoplasm.

In another embodiment, the invention relates to a composition containing a compound ofthe Formula I, a pharmaceutically acceptable sait, solvaté, or prodrug thereof and an anti- 30 neoplastic agent as a combined préparation for the sïmultaneous, separate or sequential use intreating a neoplasm wherein the anti-neoplastic agent is selected from the group consisting ofalkylating agents, antibiotics and plant alkaloids, hormones and steroids, synthetic agents havinganti-neoplastic activity, antimetabolites and biological molécules having anti-neoplastic activity. in another embodiment, the invention relates to a composition containing a compound of 35 the Formula I, a pharmaceutically acceptable sait, solvaté, or prodrug thereof and an anti-neoplastic agent as a combined préparation for the sïmultaneous, separate or sequential use intreating a neoplasm wherein the anti-neoplastic agent is selected from the group consisting of 20

Ara-c, VP-16, cis-platin, adriamycin, 2-chloro-2-deoxyadenosine, 9- (3-D-arabinosyl-2-fluoroadenine, carboplatin, gemcitabine, camptothecin, paclitaxel, BCNU, 5-fluorouracil,irinotecan, and doxorubicin.

Another object of the invention is to provide a method for the treatment of neoplasms.

In an embodiment, the invention relates to a method for treating a neoplasm which comprises administering to a mammal in need thereof, an anti-neoplastic agent in combinationwith a compound of the Formula I, a pharmaceutically acceptable sait, solvaté, or prodrug thereof. in another embodiment, the invention relates to a method for treating a neoplasm whichcomprises administering to a mammal in need thereof, an anti-neoplastic agent in combinationwith a compound of the Formula I, a pharmaceutically acceptable sait, solvaté, or prodrug thereof,wherein the anti-neoplastic agent is selected from the group consisting of Ara-c, VP-16, cis-platin,adriamycin, 2-chloro-2-deoxyadenosine, 9-p-D-arabinosyl-2-fluoroadenine, carboplatin,gemcitabine, camptothecin, paclitaxel, BCNU, 5-fluorouracil, irinotecan, and doxorubicin. Inanother embodiment, more than one anti-neoplastic agents may be used in combination with a compound of the Formula I, the pharmaceutically acceptable salts, solvatés, or prodrugs thereof.Another object of the invention is to provide methods for enhancing the anti-neoplastic effect of therapeutic radiation.

In an embodiment, the invention relates to a method for treating a neoplasm whichcomprises administering to a mammal in need thereof, therapeutic radiation having an anti-neoplastic effect in combination with a compound of the Formula I, a pharmaceutically acceptablesait, solvaté, or prodrug thereof.

Another object of the invention is to provide methods for enhancing the antineoplasticeffect of an anti-neoplastic agent.

In an embodiment, the invention relates to a method for enhancing the anti-neoplasticeffect of an anti-neoplastic agent in a mammal which comprises administering to a mammal inneed thereof, a compound of the Formula I, a pharmaceutically acceptable sait, solvaté, orprodrug thereof, in combination with an antineoplastic agent. The antineoplastic agents includealkylating agents, antibiotics and plant alkaloids, hormones and steroids, synthetic agents havinganti-neoplastic activity, antimetabolites and biological molécules having anti-neoplastic activity.Spécifie antineoplastic agents include Ara-c, VP-16, cis-platin, adriamycin, 2-chloro-2-deoxyadenosine, 9-p-D-arabinosyl-2-fluoroadenine, carboplatin, gemcitabine, camptothecin,paclitaxel, BCNU, 5-fluorouracil, irinotecan, and doxorubicin.

In another embodiment, the invention relates to a method for enhancing the anti-neoplastic effect of therapeutic radiation in a mammal which comprises administering to amammal in need thereof, a compound of the Formula I, a pharmaceutically acceptable sait,solvaté, or prodrug thereof, in combination with therapeutic radiation having an anti-neoplasticeffect. 013017 21

Another object of the invention is to provide a method for the treatment of a conditionwhich can be treated by the inhibition of protein kinases. In one embodiment of the invention, theprotein kinases are selected from the group consisting of Checkpoint kinase 1 (CHK-1),Checkpoint kinase 2 (CHK-2), Cyclin dépendent kinase 1 (CDK1), Sérum and glucocorticoidregulated kinase (SGK), Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK),Lymphoid T cell tyrosine kinase (LCK), Mitogen activated protein kinase-2 (MAPK-2), Mitogen-and stress-activated protein kinase 1 (MSK1), Rho kinase (ROCK-II), P70 S6 kinase (p70S6K),cAMP (adenosine 3',5’cyclic monophosphate)-dependent protein kinase (PKA), Mitogen activatedprotein kinase (MAPK), Mitogen activated protein kinase-1 (MAPK-1), Protein kinase C-relatedkinase 2 (PRK2), 3'-Phosphoinositide dépendent kinase 1 (PDK1), Fyn kinase (FYN), Proteinkinase C (PKC), Protein Kinase C Beta 2 (ΡΚΟβΙΙ), Protein Kinase C Gamma (PKCy), Vascularendothélial growth factor receptor 2 (VEGFR-2), Fibroblast growth factor receptor (FGFR),Phosphorylase kinase (PHK), Wee1 kinase (Wee1), and Protein Kinase B (PKB). Preferably, theprotein kinases are selected from the group consisting of Checkpoint kinase 1 (CHK-1),Checkpoint kinase 2 (CHK-2), Mitogen activated protein kinase (MAPK), Mitogen activated proteinkinase-1 (MAPK-1), Mitogen activated protein kinase-2 (MAPK-2), Vascular endothélial growthfecfor receptor 2 (VEGFR-2), Fibroblast growth factor receptor (FGFR), Phosphorylase kinase(PHK), Protein Kinase B alpha (PKBa), and Wee1 kinase(Wee1).

In an embodiment, the invention relates to a method for the treatment of a condition whichcan be treated by the inhibition of protein kinases in a mammal, including a human, comprisingadministering to a mammal in need thereof, a compound of the Formula I, a pharmaceuticallyacceptable sait, solvaté, or prodrug thereof.

In another embodiment, said condition which can be treated by the inhibition of proteinkinases is selected from the group consisting of connective tissue disorders, inflammatorydisordersjmmunology/allergy disorders, infectious diseases, respiratory diseases, cardiovasculardiseases, eye diseases, metabolic diseases, central nervous System (CNS) disorders, liver/kidneydiseases, reproductive health disorders, gastric disorders, skin disorders and cancers.

Other aspects, advantages, and preferred features of the invention will become apparentfrom the detailed description below.

Detailed Description And Preferred Embodiments of The Invention

For purposes of the présent invention, as disclosed and claimed herein, the followingterms and abbreviations are defined as follows:

Unless otherwise indicated, the term "wherever it occurs" refers to any occurrence of anyfunctional groups (such as R1, R2 or any substituents thereof), including any occurrence of anycomponent of any functional groups referred to herein (e.g., the “(Ci-C8)alkyl component of (CrC8)alkyl-O-). 0130 Π 22

Unless otherwise indicated, the term "(C1-C8)alkyl" as well as the (C1-CB)alkyl componentof other terms referred to herein (e.g., the "(Ci-Cs)alkyl component of (Ci-C8)alkyl-O-), may belinear or branched (such as methyl, ethyf, n-propyl, /sopropyt, n-butyl, /so-butyl, seconda/y-butyl,ferf/a/y-butyl).

Unless otherwise indicated, the term "(C2-C8)alkenyl" means straight or branchedhydrocarbon radical, substituent, moiety, or sub-moiety referred to herein having 2 to 8 carbonatoms having at least one double bond including, but not limîted to ethenyl, 1-propenyl, 2-propenyl(allyl), Zso-propenyl, 2-methyl-1-propenyl, 1-butenyl, or2-butenyl.

Unless otherwise indicated, the term "(C2-C8)alkynyl” is used herein to mean straight orbranched hydrocarbon radical, substituent, moiety, or sub-moiety referred to herein having 2 to 8carbon atoms having one triple bond including, but not limited to, ethynyl (-CaC-H), propynyl(-CH2-CaC-H or-C=C-CH3), or butynyl (-CH2-CH2-C=C-H, or -CH2-C=C-CH3, or -CsC-CH2CH3).

Unless otherwise indicated, the term “(C3-C10)cycloalkyl" refers to a non-aromatic,saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclichydrocarbon radical, substituent, moiety, or sub-moiety referred to herein containing a total offrom 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary (C3-C10)cycloalkylsinclude monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Illustrative examples of (C3-Cio)cycloalkyl are derived from, but not limited to, the following:

□. o.œ

Unless otherwise indicated, the term “(C2-C10)heterocyclyr réfers to a non-aromatic,saturated or partially saturated, monovalent, monocyclic or fused, spiro or unfused bicyclic ortricyclic radical, substituent, moiety, or sub-moiety referred to herein containing a total of from 2 to10 ring carbon atoms and 1 to 5 ring heteroatoms selected from nitrogen, oxygen and sulfur.Illustrative examples of (C2-C10)heterocyclyl include azetidinyl, pyrrolidyl, piperidyl, piperazinyl,morpholinyl, chromenyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, azabicyloI4.3.0]nonyl, 013017 23 oxabicyclo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like. Additional illustrative examples of(C2-Cio)heterocyclyl are derived from, but not limited to, the following:

o H

unless otherwise indicated, the foregoing (C2-C10)heterocyclyl can beC-attached or N-attached where such is possible. For instance, piperidyl can be piperid-1-yl(N-attached) or piperid-2-yl (C-attached). 10 Unless otherwise indicated, the term “(C6-C10)aryr refers to an aromatic, monovalent, monocyclic or fused or unfused bicyclic or tricyciic radical, substituent, moiety, or sub-moietyreferred to herein containing a total of from 6 to 10 ring carbon atoms. Illustrative examples of(C6-Cio)aryl are derived from, but not limited to, the following:

15 Unless otherwise indicated, the term “(Ci-Cio)heteroaryl” refers to an aromatic, monovalent monocyclic, fused or unfused bicyclic or tricyciic radical, substituent, moiety, or sub- 013017 24 10 moiety referred to herein containing a total of from 1 to 10 ring carbon atoms and 1 to 5 ringheteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of (CfC10)heteroaryl include, but not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl,furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl,naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl,quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazlnyl, isothiazolyl,phenothiazinyl, and phenoxazinyl. Further examples of (CrCio)heteroaryl are derived from, butnot limited to, the following:

15 20 unless otherwise indicated, the foregoing (Ci-C10)heteroaryl can beC-attached or N-attached where such is possible. For instance, pyridyl can be pyrid-1-yl(N-attached) or pyrid-3-yl (C-attached).

Unless otherwise indicated, the term ,\(C3-C1o)cycloalky1)((C1-CB)alkyl)>N-“ refers to aradical, substituent, moiety, or sub-moiety referred to herein having the formula: (C3-C10)cycloalkylk (CrC8)alkyl) wherein the terms '‘(C3-Cio)cycloalkyl” and “(CrCeJalkyl” are as defined above.

Unless otherwise indicated, the term ,‘((C6-C1o)aryl)((Ci-Ce)alkyl)>N-‘' refers to a radical,substituent, moiety, or sub-moiety referred to herein having the formula: (CB-Cio)aryl)\ (CrCeialkyl)/ N-f wherein the terms "(C6-Cio)aryr and “(C^Cgjalkyl” are as defined 25 above. 013017 25

Unless otherwise indicated, the term “(C1-C10)heteroaryl-NH-‘' refers to a radical,substituent, moiety, or sub-moiety referred to herein having the formula: (CrC10)heteroaryl)v

H ; wherein the term "(Ci-C10)heteroaryl” is as defined above and wherein said (C1-C10)heteroaryl is bonded to the -NH- via a ring (CrC10)heteroaryl carbon atom.Unless otherwise indicated, the term “(C2-C10)heterocyclyl-NH-“ refers to a radical, substituent, moiety, or sub-moiety referred to herein having the formula: (C2-C10)heterocyclyl) H'

; wherein the term “(C2-C10)heterocyclyl” is as defined above and 10 10 15 15 20 20 25 25 wherein said (C2-C10)heterocyclyl is bonded to the -NH- via a ring (C2-C10)heterocyclyl carbonatom.

The term “a pharmaceuticaliy acceptable sait” refers to a sait that retains the biologicaleffectiveness of the free acids and bases of the specified compound and that is not biologically orotherwise undesirable. A compound of the invention may possess a sufficiently acidic, asufficiently basic, or both functional groups, and accordingly react with any of a number ofinorganic or organic bases, and inorganic and organic acids, to form a pharmaceuticaliyacceptable sait. Exemplary pharmaceuticaliy acceptable salts include those salts prepared byreaction of the compounds of the présent invention with a minerai or organic acid or an inorganicbase, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acétates, propionates, decanoates, caprylates, acrylates, formates,isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methane-sulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

The term “prodrug”, as used herein, refers to a metabolic precursor of a compound ofthe Formula I (or a sait thereof) that is pharmaceuticaliy acceptable. A prodrug may be inactivewhen administered to a subject but is converted in vivo to an active compound of the Formula I.The term “active métabolite”, as used herein, refers to a metabolic product of a compound of theFormula I that is pharmaceuticaliy acceptable and effective. Prodrugs and active métabolites ofcompounds of the Formula I may be determined using techniques known in the art. Prodrugs andactive métabolites of a compound may be identified using routine techniques known in the art.See, e.g., Bertoiini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Soi., 86(7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 013017 26 224-331 (1984); Bundgaard, Design of Prodruqs (Elsevier Press 1985); and Larsen, Design andApplication of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds.,Harwood Academie Publishers, 1991).

The CHK-1 inhibitor of the présent invention may be administered in combination withother anti-neoplasm thérapies including anti-neoplastic agents and radiation therapy.

The term "in combination with" means that the compound of Formula I may beadministered shortly before, shortly after, concurrently, or any combination of before, after, orconcurrently, with such other anti-neoplasm thérapies. Thus, the compound and the anti-neoplastic agent may be administered simultaneously as either as a single composition or as twoseparate compositions or sequentially as two separate compositions. Likewise, the compoundand radiation therapy may be administered simultaneously, separately or sequentially. Thecompound may be administered in combination with more than one anti-neoplasm therapy. In apreferred embodiment, the compound may be administered from 2 weeks to 1 day before anychemotherapy, or 2 weeks to 1 day before any radiation therapy. In another preferredembodiment, the CHK-1 inhibitor may be administered during anti-neoplastic chemotherapies andradiation thérapies. If administered following such chemotherapy or radiation therapy, the CHK-1inhibitor may be given within 1 to 14 days following the primary treatments. The CHK-1 inhibitormay also be administered chronically or semi-chronically, over a period of from about 2 weeks toabout 5 years. One skiiled in the art will recognize that the amount of CHK-1 inhibitor to beadministered in accordance with the présent invention in combination with other antineoplasticagents or thérapies is that amount sufficient to enhance the anti-neoplasm effects of anti-neoplastic agents or radiation thérapies or that amount sufficient to induce apoptosis or cell deathalong with the anti-neoplastic or radiation therapy and/or to maintain an antiangiogenic effect.Such amount may vary, among other factors, depending upon the size and the type of neoplasia,the concentration of the compound in the therapeutic formulation, the spécifie anti-neoplasmagents used, the timing of the administration of the CHK-1 inhibitors relative to the otherthérapies, and the âge, size and condition of the patient.

The term “protein kinases”, as used herein, refers to enzymes that catalyze thephosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Theconséquences of this seemingly simple activity are staggering; cell growth, différentiation andprolifération, Le., virtually ail aspects of cell life in one way or another dépend on the proteinkinase activity. Furthermore, abnormal protein kinase activity has been related to a host ofdisorders, ranging from relatively non-life threatening diseases such as psoriasis to extremelyvirulent diseases such as glioblastoma (brain cancer). The protein kinases can be convenientlybroken down into two major classes, the protein tyrosine kinases (PTKs) and the serine-threoninekinases (STKs). In addition, a third class of dual specificity kinases which can phosphorylate bothtyrosine and serine-threonine residues is known. Examples of protein kinases and their isoforms i ♦» ; ι 27 contemplated within this invention include, but are not limited to, Checkpoint kinase 1 (CHK-1),Checkpoint kinase 2 (CHK-2), Cyclin dépendent kinase 1 (CDK1), Sérum and glucocorticoidregulated kinase (SGK), Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK),Lymphoid T cell tyrosine kinase (LCK), Mitogen activated protein kinase-2 (MAPK-2), Mitogen-and stress-activated protein kinase 1 (MSK1), Protein Kinase B (PKB), Protein Kinase B alpha(PKBa), Rho kinase (ROCK-II), P70 S6 kinase (p70S6K), cAMP (adenosine 3',5' cyclicmonophosphate)-dependent protein kinase (PKA), Mitogen activated protein kinase-1 (MAPK-1),Protein kinase C-related kinase 2 (PRK2), 3'-Phosphoinositide dépendent kinase 1 (PDK1), Fynkinase (FYN), Protein kinase C (PKC), Protein Kinase C Beta 2 (PKCpil), Protein Kinase CGamma (PKCy), Vascular endothélial growth factor receptor 2 (VEGFR-2), Fibroblast growthfactor receptor (FGFR), Phosphorylase kinase (PHK), Wee1 kinase (Wee1), and Protein Kinase B(PKB).

Checkpoint kinase 2 (CHK-2) acts as a cell cycle checkpoint controller in response toDNA damage. CHK-2 is a downstream effector of ΑΊΓΜ which phosphorylâtes p53 protein andaffects cell cycle progreesion from G-, to the S phase. CHK-2 activation also affects S phaseprogression. In addition along with CHK-1, CHK-2 influences G2/M transition and plays a rôle inapoptosis if the damage cannot be repaired. CHK-2 could play a rôle in sensitizing cancer cells toDNA-damaging thérapies. CHK-2 may also play a rôle as a tumor suppressor. Bartek, J. et. al.(2001) Nature Reviews, Molecular Cell biology 2:877-886.

Cyclin dépendent kinase 1 (CDK1) is also known as Cdc2 in yeast cells. The cell cycledirects spécifie events that control growth and prolifération of cells. The cyclin B/Cdk1 complexpromotes entry into mitosis. Cyclin B1 overexpression has been found in 90% of colorectalcarcinomas Since the cell cycle is dysregulated in human cancers, modulation of CDK activity is apossible therapy. Olomoucine, a CDK inhibitor, has been shown to inhibit cellular prolifération inhuman cancer cells. In lymphoma cells, olomoucine arrests the cell cycle in both the G1 and G2phases by inhibiting cyclin E/CDK2 and cyclin B/CDK1. Buolamwini, J.K. (2000) CurrentPharmaceutical Design 6:379-392; Fan, S. et. al. (1999) Chemotherapy 45:437-445. Sérum and glucocorticoid regulated kinase (SGK) is rapidly and highly regulated bycorticosteroids in A6 cells at the mRNA and protein levels. SGK is also induced by aldostérone inthe kidney of adrenalectomized rats. SGK is activated by 3'-phosphoinositide dépendent kinase 1(PDK1). SGK might play a critical rôle in aldostérone target cells and may be physiologicailyimportant in the early response to aldostérone. Aldostérone receptor antagoniste hâve recentlyshown great promise in clinical trials for patients with heart failure. The ability to médiate thephysiological responses to aldostérone may like-wise prove bénéficiai. See Leslie, N. R. et. al.(2001) Chemical Reviews 101(8):2365-2380; Funder, J. W. (1999) Molecular and CellularEndocrinology 151 (1 -2):1 -3; Verrey, F. et. al. (2000) Kidney International 57(4):1277-1282. 013017 28

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) isoform a2(AMPK (x2) is présent in high concentrations in skeletal muscle, heart, and liver while the <x1isoform is widely distributed. AMPK, probably the cc2 isoform, phosphorylâtes acetyl-CoAcarboxylase β isoform (ACCp)and inactivâtes it under conditions electricai stimulation orexercise. In rat skeletal muscle, malonyl-CoA is regulated by ACCpis and involved in theregulatory mechanism of transferring long chain fatty acids into the mitochondria where they areoxidized. AMPK could therefore be linked to obesity and/or insuiin résistance, and modulation ofAMPK could be potentially bénéficiai in the treatment of these diseases. AMPK inhibits enzymesinvolved in glycogen and cholestérol synthesis. It is a possible regulatory enzyme that in responseto adenosine 5'-triphosphate (ATP) déplétion, reduces further ATP consumption by initiatingcellular adjustments that are directed toward maintaining ATP levels. In addition, AMPK has beenKnked to transcription , régulation of créatinine kinase, apoptosis, and glucose transport SeeKemp, B. E. et al. (1999) Trends in Biochemical Sciences 24(1):22-25; Friedman, J. (2002)Nature 415(6869):268-269,· Ruderman, N. B. et al. (1999) American Journal of Physiology 276(1,Pt 1):E1-E18.

Lymphoid T cell tyrosine kinase (LCK) is a cytosolic non-receptor tyrosine kinase and a T-lymphocyte member of the Src family. LCK has been implicated in early phase T-cell receptoractivation by antigens and plays a critical rôle in T-cell mediated immune responses. Uponactivation by autophosphorylation, LCK phosphorylâtes T-cell receptor ξ-chains which can thenrecruit a second cytoplasmic protein-tyrosine kinase ZAP-70 to promote T-cell activation.Inhibitors could be used for the treatment of rheumatoid arthritis, diseases related to immuneresponse and T-cell based leukemias and lymphomas. See Garcia-Echeverria, C. (2001) CurrentMédicinal Chemistry 8(13):1589-1604; Majolini, Μ. B. eL al. (1999) Leukemia & Lymphoma35(3/4):245-254.

Mitogen- and stress-activated protein kinase 1 (MSK1) is activated on stimulation of theRas-mitogen activated protein kinase (MAPK) pathway and also by the p38 stress kinasepathway. Both pathways are implicated in tumorigenesis. Stimulation of the Ras-MAPK signaltransduction pathway by growth factors or phorbol esters results in phosphorylation of histone H3.MSK1 has been shown to médiate epidermal growth factor (EGF) or TPA (12-0- tetradecanoylphorbol-13-acetate, a phorbol ester) induced phosphorylation of H3. There is « evidence that persistent activation of Ras-MAPK pathway and MSK1 resulting in elevatedphosphorylated H3 levels may contribute to aberrant gene expression observed in oncogene-transformed cells. Inhibition of MSK1 suppressed the induction of c-fos (proto-oncogene) and uPAgenes in parental and oncogene-transformed cells. Both c-fos and uPA are involved in tumorinvasion and metastasis. See Strelkov, I. et. al. (2002) Cancer Research 62(1):75-78; Zhong, S.et. al. (2001) Journal of Biological Chem/sf/y 276(35):33213-33219; Nomura, M. et. ai. (2001)Journal of Biological Chemistry 276(27):25558-25567. 013017 29

Rho kinase (ROCK-II) is also known as ROKa. By inhibiting ROCK-II, one couldpotentially influence Rho GTPases which act as molecular Controls that regulate many essentialcellular processes, including actin dynamics, cell-cycle progression, and cell adhesion. The in vitroand in vivo biological effects of Y-27632, a spécifie inhibitor of ROCK, hâve been described in theliterature and include lowering blood pressure in hypertensive rats, inhibition of Rho-inducedformation of stress fibers and focal adhesions, and inhibition of tumor growth. See Narumiya, S.et. al(2000) Methods in Enzymology 325 (Regulators and Effectors of Small GTPases, Part D):273-284 (and associated référencés listed therein); Bishop, et al. (2000) Biochem. J. 348: 241-255. P70 S6 kinase (p70seK) is found as two isoforms-one cytoplasmic and the other in thenucléus. They are similar except for N-terminus, and both are called p70S6K or S6K1. A secondfunctional homologue S6K2 was also identified. P70SSK is a downstream target of the lipid kinasephosphoinositide 3-OH kinase (PI(3)K). P70S6K is implicated in cell cycle control and neuronal celldifférentiation. P70S6K may also function in regulating cell motility which could influence tumormétastasés, the immune response, and tissue repair. Along with PKB/Akt, p70SSK is a crucialeffector in oncogenic protein-tyrosine kinase (PTK) signaling. P70SSK may be a more potent kinasefor BAD than PKB/Akt (see above) in response to insulin growth factor 1 (IGF-1) stimulation.P70SSK may therefore play an important antiapoptotic raie. See Blume-Jensen, P. et. al. (2001)Nature 411(6835):355-365; Accili, D. (2001) Journal of Clinical Investigation 108(11 ):1575-1576;Hidalgo, M. et al. (2000) Oncogene 19(56):6680-6686; Berven, L. et. al. (2000) Immunology andCell Biology 78(4):447-451. cAMP (adenosine 3',5' cyclic monophosphate)-dependent protein kinase (PKA) isinvolved in a wide range of physiological responses following interaction with cAMP. cAMP is asecond messenger that régulâtes many different cellular activities such as gene transcription, cellgrowth and différentiation, ion channel conductivity, and release of neurotransmitters. ThecAMP/PKA interaction acts as a major regulatory mechanism in mammals, and PKA has beenshown phosphorylate a myriad of physiological substrates. PKA has two major isoforms- PKAIand PKAII. PKAI inhibitors hâve shown enhancing effects when used in combination certaincytotoxic cancer thérapies. Antisense oligonucleotides targeting the PKAI subunit Rla hâve shownenhanced anti-tumor effects when combined with Taxol. Glucagon activâtes PKA and PKA mayinfluence insulin response along with calmodulin-dependent protein kinase and protein kinase C.PKA is involved in regulating cardiac L-type calcium channels, and modulation of the implicatedregulatory pathways may prove useful in the treatmentof heart disease. In addition, dysfunctionalT-cells isolated from HIV patients hâve been restored by the addition of PKAI antagoniste. SeeSkalhegg, B.S. et. al. (2000) Frontiers in Bioscience [Electronic Publication] 5:D678-D693;Brandon, E. P. et. al. (1997) Current Opinion in Neurobiology 7(3):397-403; Nesher, R. et.al.(2002) Diabètes 51 (Suppl. 1): S68-S73; Shabb, J. B. (2001) Chemical Reviews 101(8):2381- 013017 30 2411; Kamp, T.J. et al. (2000) Circulation Research 87(12); 1095-1102; Tortora, G. étal. (2002)Clinical Cancer Research 8:303-304; Tortora, G. étal. (2000) Clinical Cancer Research 6:2506-2512.

Mitogen activated protein kinase (MAPK) is also known as ERK. In tumorigenesis, rasoncogenes transmit extracellular growth signais. The MAPK pathway is an important signalingroute between membrane-bound ras and the nucléus. A phosphorylation cascade involving threekey kinases is involved. They are Raf, MEK (MAP kinase kinase) and MAPKZERK. Raf isoformsphosphorylate and activate isoforms MEK1 and MEK2. MEK1 and 2 are dual specificîty kinasesthat in turn phosphorylate and activate the .MAPK isoforms MAPK1/ERK1 and MAPK2/ERK2. Infibroblasts, MAPK1/ERK1 and MAPK2/ERK2 are both strongly activated by growth factors and bytumor-promoting phorbol esters. MAPK1/ERK1 and MAPK2/ERK2 are also involved with glucoserégulation, neurotransmitter régulation, and secetagogue régulation (in endocrine tissues). TheMAPK pathway has also been linked to the induction of cydin D1 mRNA and thus linked to G1phase of cell cycle. See Webb, C.P. et. al. (2000) Cancer Research 60(2), 342-349; Roovers, K.et al. (2000) BioEssays 22(9):818-826; Chen, Z. et. al. (2001) Chemical Reviews 101(8):2449-2476; Lee, J. C. et. al. (2000) Immunopharmacology 47(2-3):185-201, Sebolt-Leopold J.S. (2000)Oncogene 19:6594-6599; Cheng, F.Y. et. al. (2001) Journal of Biological Chemistry276(35):32552-32558; Cobb, M.H.et. al. (2000) Trends in Biochemical Sciences 25(1):7-9; Cobb,M.H.et. al. (1995) Journal of Biological Chem/sf/y 270(25):14843-14846; Deak, M. et. al. (1998)EMBO Journal 17(15):4426-4441 ; Davis, J.D. (1993) Journal of Biological Chemistry268(20):14553-14556. cSrc (also known as p60 c-src) is cytosolic, non-receptor tyrosine kinase. c-Src isinvolved in the transduction of mitogenic signais from a number of polypeptide growth factorssuch as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). c-Src is overexpressed in mammary cancers, pancreatic cancers, neuroblastomas, and others. Mutant c-Srchas been identified in human colon cancer. c-Src phosphorylâtes a number of proteins that areinvolved in regulating cross-talk between the extracellular matrix and the cytoplasmic actincytoskeleton. Modulation cSrc activity could hâve implications in diseases relating to cellprolifération, différentiation and death. See Bjorge, J.D. et. al. (2000) Oncogene 19(49):5620-5635; Halpern, M. S. et. al. (1996) Proc. Natl. Acad. Sci. U. S. A. 93(2), 824-7; Belsches, A.P. et.al. (1997) Frontiers in Bioscience [Electronic Publication] 2:D501-D518; Zhan, X. et. al (2001)Chemical Reviews 101:2477-2496; Haskell, M.D. et. al. (2001) Chemical Reviews 101:2425-2440;

Protein kinase C-related kinase 2 (PRK2) is regulated by the G-protein Rho. PRK2 isfound in régions of large actin turnover. Endogenous PRK2 kinase activity increases withkératinocyte différentiation and is associated with kératinocyte cell-cell adhesion and Fyn kinaseactivation. See Gross, C., et. al. (2001) FEBS Letters 496(2,3): 101-104; Calautti, E. et. al. (2002)Journal of Cell Biology 156(1 ): 137-148. 013017 31 3'-Phosphoinositide dépendent kinase 1 (PDK1) phosphorylâtes and activâtes membersof the AGC (cAMP-dependent, cGMP-dependent, and protein kinase C) kinase family that areactivated downstream of phosphoinositide 3-kinase (PI3K), PI3K becomes active through insulinstimulation. PDK1 activâtes a number of protein kinases and therefore can be connected to the 5 régulation of a number of insulin spécifie events. PDK1 phosphorylation and activation of PKCÇ isnecessary for insulin-dependent GLUT4 translocation. Insulin-induced GLUT4 translocation isphysiologically related to the actin-based cytoskeleton. Disturbances in actin filaments hâve beenlinked to loss of insulin effect on glucose transport and decreased translocation of GLUT4. SeeWick, K. L. et. al. (2001) Current Drug Targets: Immune, Endocrine and Metabolic Disorders 10 1 (3):209-221 ; Peterson, R. T. et. al. (1999) Current Biology 9(14):R521-R524; Toker, A. et al. (2000) Ce/f 103(2): 185-188; Leslie, N.R. (2001) Chem. Rev. 101: 2365-2380.

Fyn kinase (FYN) is a member of the Src family of tyrosine kinases. Fyn has beenimplicated in positive contrai of kératinocyte cell-cell adhesion. Adhesion plays a crucial function inestablishment and maintenance of organized tissues. Fyn knockout and transgenic mice 15 established that Fyn participâtes in T cell receptor (TCR) signaling. Overexpression of the fyn(T)transgene produces T celle with enhanced responsiveness to TCR signaling. Conversely,expression of an inactive kinase form is inhibitory. Fyn may be an appropriate target for treatmentof autoimmune diseases. Fyn -/- mice are hypersensitive to alcohol which suggests that Fyn mightbe a target for the treatment of alcoholism. Alteration of Fyn levels may also aid in the treatment of 20 skin disorders. Fyn has been implicated in the régulation of programmed cell death, and Fyn-/-mice exhibit reduced apoptosis. See also PRK2. See Calautti, E. et al. (2002) Journal of CellBiology 156(1 ):137-148; Resh, M. D. (1998) Journal of Biochemistry & Cell Biology 30(11):1159-1162.

Vascular endothélial growth factor receptor 2 (VEGFR-2) is also known as FLK-1 and as 25 KDR (kinase insert domain receptor). Other VEGF receptor tyrosine kinases include VEGFR-1 (Flt-1) and VEGFR-3 (Flt-4). Angiogenesis or the development of new vasculature is central tothe process by which solid tumors grow. The degree of vasculaturization has been linked withincreased potential for metastasis. VEGFR-2, expressed only on endothélial cells, binds thepotent angiogenic growth factor VEGF and médiates the subséquent signal transduction. 30 Inhibition of VEGF-R2 activity has resulted in decreased angiogenesis and tumor growth in in vivomodels, and inhibitors of VEGFR-1 are currently in clinical trials for the treatment of cancer. SeeStrawn et al.,(1996) Cancer Research 56:3540-3545; Millauer et al.,(1996) Cancer Research56:1615-1620; Sakamoto, K. M. (2001) IDrugs 4(9):1061-1067; Eliis, L. M. et.al. (2000) Oncologist5(Suppl. 1):11-15; Mendel, D.B. et. al (2000) Anti-Cancer Drug Design 15:29-41; Kumar, C.C. 35 étal. (2001) Expert Opin. Emerging Drugs 6(2):303-315; Vajkoczy, P. et. a! (1999) Neoplasia1(1):31-41. 013017 32

Fibroblast growth factor receptor (FGFR) binds the angiogenic growth factors aFGF andbFGF and médiates subséquent intracellular signal transduction. Growth factors such as bFGFmay play a critical rôle in inducing angiogenesis in solid tumors that hâve reached a certain size.FGFR is expressed in a number of different cell types throughout the body and may or may not 5 play important rôles in normal physiological processes in adult humans. Systemic administrationof a small-molecule inhibitor of FGFR has been reported to block bFGF-induced angiogenesis inmice. See Yoshiji et al., (1997) Cancer Research 57: 3924-3928; Mohammad étal., (1998) EMBOJournal 17:5996-5904.

Phosphorylase kinase (PHK) activâtes glycogen phosphorylase. The primary10 conséquence of this activation is to release glucose 1-phosphate from glycogen. Conversion toglycogen is the major means by which glucose is stored in mammals. Intracellular glycogen storesare used to maintain blood-glucose homeostasis during fasting and are a source of energy formuscle contraction. In Vivo, PHK is phosphorylated by cAMP-dependent protein kinase (PKA)which increases the spécifie activity of PHK. Both Type 1 and 2 diabetics show reduced glycogen 15 levels in liver and muscle cells, Glycogen levels are tightly regulated by hormones and metabolicsignaling. Kinase inhibitors that could augment intracellular glycogen levels may prove bénéficiaiin the treatment of diabètes. See Brushia, R.J. et.al. (1999) Frontière in Bioscience [ElectronicPublication] 4:D618-D641; Newgard, C.B. et. al. (2000) Diabètes 49:1967-1977; Venien-Bryan, C.et al. (2002) Structure 10:33-41; Graves, D. et. al. (1999) Pharmacol. Ther. 82:(2-3)143-155; 20 Kilimann, M.W. (1997) Protein Dvsfunction and Human Genetic Disease Chapter 4:57-75.

Wee1 kinase (Wee1) along with Mik1 kinase has been shown to phosphorylate Cdc2.

Phosphorylation of Cdc2 has been shown to prevent mitotic entry. Wee1 may play an importantrôle the normal growth cycle of cells and may be implicated in cell-cycle checkpoint control. Rhind,N. et al. (2001) Molecularand Ceffu/arS/o/ogy 21 (5): 1499-1508. 25 Protein Kinase B (PKB) is also known as Akt. There are three very similar isoforms known as PKB q β. and γ (or Akt 1, 2, and 3). Ultraviolet irradiation in the 290-320nM range has beenassociated with the harmful effects of sunlight. This irradiation causes activation of PKB/Akt andmay be implicated in tumorigenesis. Over expressed PKB/Akt has been shown in ovarian,prostate, breast & pancreatic cancers. PKB/Akt is also involved in cell cycle progression. PKB/Akt 30 promûtes cell survival in a number of ways. It phosphorylâtes the proapoptotic protein, BAD, sothat it is unable to bind and inactivate the antiapoptotic protein Bcl-xl. PKB/Akt also serves toinhibit apoptosis by inhibiting caspase 9 and forkhead transcription factor and by activating IkBkinase. See Barber, A.J. (2001) Journal ofBiological Cbem/siry 276(35):32814-32821 ; Medema,R.H. et al. (2000) Nature 404:782-787; Muise-Helmericks, R.C. et. al (1998) Journal of Biological 35 Chemistry 273(45): 29864-29872; Nomura, M. et. al. (2001) Journal of Biological Chemistry 276(27): 2558-25567; Nicholson, K. M. et.al. (2002) Cellular Signaling 14(5): 381-395; Brazil, 33 D.P. et. al. (2001) Trends in Biochemical Sciences 26(11): 657-664. Leslie, N.R. (2001) ChemRev 101:2365-2380.

Protein kinase C (PKC) classical isoforms are designated α,β1, β2 and γ and ail are Ca2+dépendent. PKC isoforms are involved in signal transduction pathways linked to a number of 5 physiological responses including membrane transport, cellular différentiation and prolifération,organization of cytoskelêtal proteins and gene expression. Tumor promoting phorbol estersactivate classical PKC isoforms and antisense oligonucleotides can block this activation. PKCisoforms are often over expressed in various cancers. PKC inhibitors hâve been shown to reversep-glycoprotein-mediated multi-drug résistance and can increase intracellular concentrations of 10 other anti-cancer agents. In myocytes, PKC isoforms hâve been implicated in certain cardiacpathologies. PKC-γ is highly expressed in brain and spinal cord and is primarily localized indendrites and neuron cell bodies. ΡΚΟ-β2 is involved in cell prolifération and overexpressionincreases sensitivity to cancer. ΡΚόβ inhibitors are a potential new therapy for diabetic retinopathywith clinical trials ongoing. See Magnelli, L. et. al. (1997) Journal of Cancer Research and Clinical 15 Oncology 123(7):365-369; Clerk, A. et. al (2001) Circulation Research 89(10): 847-849; Carter, C.(2000) Current Drug Targets1(2):163-183; Greenberg, S. et al. (1998) Alcohol 16(2); 167-175;Rosenzweig, T. et al. (2002) Diabetes51(6):1921-1930; Deucher, A. et al. (2002) Journal ofBiological Chemistry 277(19):17032-17040,- Frank, R.N. (2002) American Journal ofOphthalmology 133(5):693-698; Parekh, D. et. al. (2000) EMBO Journal 19(4):496-503; Newton, 20 A.C. (2001 ) Chem. Rev. 101:2353-2364.

The term "treating" or “treated”, as used herein, refers to reversing, alleviating, inhibiting the pragress of, or preventing the disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above. 25 “Connective tissue disorders” as used herein refers to disorders such as degenerative cartilage loss following traumatic joint injury, osteoarthritis, osteoporosis, Paget’s disease,loosening of artificial joint implants, periodontal disease and gingivitis. “Destruction of articuler cartilage" as used herein refers to connective tissue disordersresulting in articuler cartilage destruction, preferably joint injury, reactive arthritis, acute 30 pyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvénile rheumatoid arthritis, morepreferably osteoarthritis. “lnflammatory disorders” as used herein refera to disorders such as rheumatoid arthritis,ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, goût, inflammatory boweldisease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia. 35 “Immunology/allergy disorders” as used herein refera to disorders such as organ transplant toxicity, allergie reactions, allergie contact hypersensitivity, autoimmune disorders such 013017 34 as those disorders associated with granulomatous inflammation/tissue remodeling (such asasthma), immunosuppression and sarcoid. "Infectious diseases,’’ including those mediated by viruses, bacteria, fungi ormycobacterial infection, as used herëin refers to disorders such as septic arthritis, AIDS, fever;Prion diseases, myasthenia gravis, Malaria, sepsis, hémodynamie shock and septic shock. “Respiratory diseases” as used herein refers to disorders such as chronic obstructivepulmonary disease (including emphysema), acute respiratory distress syndrome, asthma,hyperoxic alveolar injury and idiopathic pulmonary fibrosis and other fibrotic lung diseases. "Cardiovascular diseases” as used herein refers to disorders such as atherosclerosisincluding atherosclerotic plaque rupture; aortic aneurysm including abdominal aortic aneurysmand brain aortic aneurysm; congestive heart failure; myocardial and cérébral infarction; stroke;cérébral ischemia; coagulation and acute phase response; left ventricular dilation; post ischémiereperfusion injury; angiofibromas; hemangiomas; and restenosis. “Eye diseases” as used herein refers to disorders such as aberrant angiogenesis, ocularangiogenesis, ocular inflammation, keratoconus, Sjogren’s syndrome, myopia, ocular tumors,corneal graft rejection, corneal injury, neovascular glaucoma, comeal ulcération, corneal scarring,macular degeneration (including “Age Related Macular Degeneration (ARMD) including both wetand dry forms), proliférative vitreoret'mopathy and retinopathy of prematurity. “Metabolic diseases” as used herein refers to disorders such as diabètes (including non-insulin dépendent diabètes meliitus, diabetic retinopathy, insuiin résistance, diabetic ulcération). “Central Nervous System" (CNS) disorders as used herein refers to disorders such ashead trauma, spinal cord injury, Inflammatory diseases of the central nervous System, neuro-degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating diseases of thenervous system, Huntington's disease, Parkinson's disease, peripheral neuropathy, pain, cérébralamyloid angiopathy, nootropic or cognition enhancement, amyotrophie latéral sclerosis, multiplesclerosis, migraine, dépréssion and anorexia. “Liver/Kidney diseases” as used herein refers to disorders such as nephrotic syndromessuch as glomerulonephritis and glomerular disease of the kidney, proteinuria, cirrhosis of the liverand interstitial nephritis. “Reproductive Health disorders" as used herein refers to disorders such asendometriosis, contraception (male/female), dysmenorrhea, dysfunctional uterine bleeding,prématuré rupture of fêtai membranes and abortifactant. “Gastric disorders" as used herein refers to disorders such as colonie anastomosis andgastric ulcers. “Skin disorders" as used herein refers to disorders such as skin aging, pressure sores,psoriasis, eczema, dermatitis, radiation damage, tissue ulcération, decubital ulcers, epidermolysisbullosa, abnormal wound healing (topical and oral formulations), burns and scleritis. 013017 35 "Cancers" as used herein refers to disorders such as solid tumor cancer including coloncancer, breast cancer, lung cancer and prostrate cancer, tumor invasion, tumor growth tumormetastasis, cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus,stomach, smail intestine, large intestine, rectum, liver and biliary passages, pancréas, larynx, 5 lung, bone, connective tissue, skin, cervix uteri, corpus endometrium, ovary, testis, bladder,kidney and other urinary tissues, eye brain and central nervous System, thyroid and otherendocrine gland, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma andhematopoietic malignancies including leukemias and lymphomas including lymphocytic,granulocytic and monocytic. 10 The following reaction Schemes illustrate the préparation of the compounds of the présent invention. Unless otherwise indicated each of A, the group -Y-Z-, X, R1, R2, R3, and R4 inthe reaction Schemes and the discussion that follows are defined as above. SCHEME 1

15 0130 1 7 36 SCHEME 2

10 013017 37

013017 38 SCHEME 4

IVa 013017 39 SCHEME δ

IVb 013017 40 SCHEME 6

0130H 41

Scheme 1 refers to the préparation of compounds of the formula I. Referring to Scheme1, a compound of formula I, wherein the group -Y-Z- has the formula -N=CH- and R2 is other thanhydrogen, can be prepared by reacting a compound of the formula II, wherein R2 is other thanhydrogen and wherein Lv is a leaving group, with hydrazine in a solvent. Suitable Lv leavinggroups include methoxy, ethoxy, or benzyloxy, preferably methoxy. Suitable solvents includealcohols (such as éthanol), preferably methanol. The aforesaid réaction can be conducted at atempérature of about 25 °C to about 90°C, preferably about 65°C. The aforesaid reaction can beconducted for a time period of about 5 minutes to about 24 hours, preferably about 0.5 hour.

Compounds of formula II, wherein R2 is other than hydrogen and wherein Lv is asdescribed above, can be prepared by reacting a compound of the formula III, wherein R2 is otherthan hydrogen and wherein Lv is as described above, with a Vilsmeier-type formylating reagent ina solvent. Suitable Vilsmeier-type formylating reagents include POCI3 and DMF or (CF3SO2)2Oand DMF; preferably POCI3 and DMF. Suitable solvents include chloroform, dioxane,tetrahydrofuran, dimethylformamide, or methylene chloride; preferably methylene chloride. Theaforesaid reaction can be conducted at a température of about 0 °C to about 25 °C, preferablyabout 0 °C during the reagent addition then allowing the reaction mixture to warm to 23 °C overabout 0.5 hour. The aforesaid reaction can be conducted for a time period of about 5 minutes toabout 24 hours, preferably about 0.5 hour.

Compounds of formula III, wherein R2 is other than hydrogen and wherein Lv is asdescribed above, can be prepared reacting a compound of formula IV, wherein Lv is as describedabove, with a compound of formula: R2-Lv1 wherein Lv1 is a leaving group, such as halo, preferably bromo or chloro, in the presence of asuitable base in a polar solvent. Suitable bases include alkoxide bases (such as sodiummethoxide, sodium ethoxide, or potassium ferf-butoxide); hydride bases (such as sodiumhydride); or carbonate bases (such as potassium carbonate or césium carbonate); preferablypotassium carbonate. Suitable polar solvents include tetrahydrofuran, dimethylformamide,dimethyl sulfoxide, or alcohols (such as éthanol), preferably dimethylformamide. The aforesaidreaction can be conducted at a température of about 0 °C to about 100 °C, preferably about 80°C. The aforesaid reaction can be conducted for a time period of about 0.5 hour to about 72hours, preferably about 24 hours. A compound Of formula I, wherein the group -Y-Z- is -O-CH2- and wherein R2 is other thanhydrogen, can be prepared by reacting a compound of formula V, wherein R2 is other thanhydrogen, wherein Pg is a protecting group, and Lv is as described above, with a Pg deprotectingagent. Suitable Pg includes phthaloy), ferf-butoxycarbonyl, benzyloxycarbonyl, or ethoxycarbonyl;preferably phthaloyl. Suitable Pg deprotecting agents include hydrazine, trifluoroacetic acid,hydrochloric acid, hydrogen chloride, hydrogen bromide in acetic acid, or hydrogen gas and Pd 013017 42 catalyst; preferably hydrazine. Acidic reactions can be neutralized after deprotection with asuitable base including tertiary amines (such as triethylamine or diisopropylethylamine) orcarbonate bases (such as potassium carbonate); preferably triethylamine. Suitable solventsinclude dimethylformamide, methyiene chloride, chloroform, or alcohol, (such as methanol),preferably methanol. The aforesaid reaction can be conducted at a température of about 20 °C toabout 130 °C, preferably about 65 °C. The aforesaid reaction can be conducted for a time periodof about 0.5 hours to about 48 hours, preferably about 2 hours. A compound of formula V, wherein R2 is other than hydrogen, wherein Pg is a protectinggroup, and Lv is as described above, can be prepared by reacting a compound of formula VI,wherein R2 is other than hydrogen, Lv2 is a leaving group and Lv is as described above, with acompound of formula

Pg-N-OH in the presence of a base in a solvent. Suitable Lv2 leaving groups include halo, toluenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, or Mitsunobu-type reaction adducts. Suitablecompounds of formula Pg-N-OH include /V-hydroxyphthalimide, tert-butyl /V-hydroxylcarbamate,N-hydroxyurethane, or benzyl W-hydroxycarbamate. Suitable bases include sodium hydride, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, tertiary amines (such as diisopropylethylamine ortriethylamine) or carbonate bases (such as sodium carbonate); preferably sodium carbonate.Suitable solvents include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methyienechloride, chloroform, or alcohol (such as methanol); preferably dimethylsulfoxide. The aforesaidreaction can be conducted at a température of about -25 °C to about 80 °C, preferably about 23°C. The aforesaid reaction can be conducted for a time period of about 5 minutes to about 48hours, preferably about 20 hours. A compound of formula VI, wherein R2 is other than hydrogen and Lv2 and Lv are asdescribed above, can be prepared by reacting a compound of formula VII, wherein R2 is otherthan hydrogen and Lv is as described above, with an Lv2 producing agent, in a solvent. SuitableLv2 producing agents inciude (C6H5)3P and CCI4; (C6HS)3P and PBr3; para-CH3C6H4SO2CI;CH3SO2CI; (CF3SO2)2O; or Mitsunobu-type reagents (such as diethyl azodicarboxylate and(C6H5)3P); preferably (C6HS)3P and CCI4. Suitable solvents include methyiene chloride, chloroform,tetrahydrofuran, carbon tetrachloride, benzene, or toluene; preferably methyiene chloride. Theaforesaid reaction can be conducted at a température of about -25 °C to about 80 °C, preferablyabout 23 °C. The aforesaid réaction can be conducted for a time period of about 5 minutes toabout 24 hours, preferably about 20 hours. A compound of formula VII, wherein R2 is other than hydrogen and Lv is as describedabove, can be prepared by reacting a compound of formula II, wherein R2 is other than hydrogenand Lv is as described above, with a reducing agent in a solvent. Suitable reducing agents includesodium borohydride, lithium borohydride, zinc borohydride, diborane, borane complexes, 013017 43 triacetoxyborohydride, sodium cyanoborohydride, or lithium cyanoborohydride; preferably sodiumborohydride. Suitable solvents include alcohol (such as methanol), tetrahydrofuran, a mixture ofmethanol and anhydrous HCl, or a mixture of methanol and acetic acid; preferably methanol. Theaforesaid reaction can be conducted at a température of about 0 °C to about 50 °C, preferablyabout 23°C. The aforesaid reaction can be conducted for a time period of about 5 minutes toabout 24 hours, preferably about 15 minutes.

Scheme 2 refers to the préparation of compounds of the formula la, which is a compoundof formula I wherein R2 is hydrogen. Referring to Scheme 2, a compound of formula la, whereinthe group -Y-Z- has the formula -N=CH-, can be prepared by reacting a compound of the formulaVIII, wherein Lv is a leaving group, as described above, with hydrazine in a solvent. The reactioncondition is as described above in the description for Scheme 1 for the préparation of a compoundof formula I from a compound of formula II.

Compounds of formula VIII, wherein Lv is as described above, can be prepared byreacting a compound of the formula IV, wherein Lv is as described above, with a Vilsmeierreagent in a solvent. The reaction condition is as described above in the description for Scheme 1for the préparation of compounds of formula II from a compound of formula III. A compound of formula la, wherein the group -Y-Z- is -O-CH2-, can be prepared byreacting a compound of formula XIV, whérein Pg2 is a protecting group, with a Pg2 deprotectingagent in a solvent. Suitable Pg2 protecting groups include fert-butoxycarbonyl, benzyloxycarbonyl,or 2-(trimethylsilyl)ethoxymethyl; preferably fert-butoxycarbonyl. Suitable Pg2 deprotecting agentsinclude trifluoroacetic acid, hydrochloric acid, hydrogen chloride, hydrogen bromide in acetic acid,hydrogen gas and Pd catalyst, or tetrabutylammonium fluoride; preferably trifluoroacetic acid.Suitable solvents include methylene chloride, chloroform, dioxane, dimethylformamide, or alcohol(such as methanol); preferably methylene chloride. The aforesaid reaction can be conducted at atempérature of about 20 °C to about 80 °C, preferably about 23 °C. The aforesaid reaction can beconducted for a time period of about 15 minutes to about 48 hours, preferably about 2 hours. A compound of formula XIV, wherein Pg2 is as described above, can be prepared byreacting a compound of formula XIII, wherein Pg is a protecting group as described in thecompound of formula V of Scheme 1, and Pg2 and Lv are as described above, with a Pgdeprotecting agent. The reaction condition is as described above in the description for Scheme 1for the préparation of a compound of formula I from a compound of formula V. A compound of formula XIII, wherein Pg2, Lv and Lv2 are as described above, can beprepared by reacting a compound of formula XII, wherein Pg2, Lv and Lv2 are as described above,with a compound of formula

Pg-N-OH 013017 44 wherein Pg is as described above, in the presence of a base in a solvent, The reaction conditionis as described above in the description for Scheme 1 for the préparation of a compound offormula V from a compound of formula VI. A compound of formula XII, wherein Pg2, Lv2 and Lv are as described above, can beprepared by reacting a compound of formula XI, wherein Pg2 and Lv are as described above, Withan Lv2 producing agent, in a solvent. The reaction condition is as described above in thedescription for Scheme 1 for the préparation of a compound of formula VI from a compound offormula VII. A compound of formula XI, wherein Pg2 and Lv are as described above, can be preparedby reacting a compound of formula IX, wherein Pg2 and Lv are as described above, with areducing agent in a solvent. The reaction condition is as described above in the description forScheme 1 for the préparation of a compound of formula VII from a compound of formula II. A compound of formula IX, wherein Pg2 and Lv are as described above, can be preparedby reacting a compound of formula VIII, wherein Lv is as described above, with a Pg2 protectingagent in the presence of a suitable base in a solvent. Suitable Pg2 protecting agents includedi-ferf-butyl dicarbonate, benzyl chloroformate, or 2-(trimethylsilyl)ethoxymethyl chloride;preferably di-Zert-butyl dicarbonate. Suitable bases include hydride bases (such as sodiumhydride, lithium hydride, or potassium hydride); preferably sodium hydride. Suitable solventsinclude tetrahydrofuran or dimethylformamide; preferably tetrahydrofuran. The aforesaid reactioncan be conducted at a température of about 0 °C to about 60 °C, preferably about 23 °C. Theaforesaid reaction can be conducted for a time period of about 15 minutes to about 24 hours,preferably about 1 hour.

Scheme 3 refers to the préparation of a compound of the formula Ib, which is acompound of the formula I wherein A is =CR1-. Referring to Scheme 3, a compound of formula lb,can be prepared by reacting a compound of the formula le, wherein halogen is selected frombromo or iodo, with a coupling reagent of the formula:

R1-M wherein M is a H or métal, in the presence of palladium and copper catalysts in a solvent. Suitablemetals include boron and tin, preferably boron. Suitable coupling reagents include Stille couplingreagent (see Chamoin, S., Houldsworth, S., Snieckus, V. Tetrahedron Lett. 1998, 39, 4175-4178incorporated herein by référencé), Suzuki coupling reagent (see Littke, A.F., Chaoyang, D., Fu,G.C. J.Am. Chem. Soc. 2000, 122, 4020-4028 incorporated herein by référencé), or Sonogashiracoupling reagent (see Sonogashira, K., Tohda, Y., Hagihara, N. Tetrahedron Lett. 1975, 16,44467-4470 incorporated herein by référencé); preferably Suzuki coupling reagent or Stillecoupling reagent. Suitable palladium and copper catalysts include Pd(C6H5)3P)4, Pd(dba)2,Pd(P(C6Hs)3)CI2 and Cul. Suitable solvents include dimethylformamide or tetrahydrofuran;preferably dimethylformamide. The aforesaid reaction can be conducted at a température of about 013017 45 22 °C to about 110 °C, preferably about 90 °C. The aforesaid reaction can be cqnducted for atime period of about 5 minutes to about 48 hours, preferably about 2 hours.

Some compounds of the formula Ib, such as those wherein R1 is a substituted alkyne (forexample methylaminopropynyl) may need additional steps requiring the use of a protecting group(for example tert-butoxycarbonyl). These protection groups and their removal processes are wellknown in the art and can be found in Greene and Wuts, "Protecting Groups in Organic Synthesis,”(John Wiley & Sons, 2nd Ed). Furthermore, compounds of the Ib, such as those wherein R1, R2 orR3 is a substituted alkyl, alkynyl, aromatic or vinyl are subjected to additional standard Chemicaltransformations (for example catalytic hydrogénation, OsCU/NMMO/NalCb, oxidative cleavage,mesylation/displacement, réductions and reductive amination). These processes are also wellknown in the art and can be found in Larock, R.C., ''Comprehensive Organic Transformations"(Wiley-VCH, 2nd Ed.). A compound of formula Ib, wherein A is =CR1- and R1 is -(C=O)-O-(Ci-Cs)alkyl, can beprepared by reacting a compound of the formula le, wherein halogen is selected from bromo oriodo, with carbon monoxide in the presence of a palladium catalyst, a base, and a compound ofthe formula H-O-(CrCe)alkyl (depending on the -(CrC6)alkyl part of the desired R1) in a solvent.Suitable palladium catalysts include Pd(dppf)CI2. Suitable bases include tertiary amine bases suchas triethylamine. Suitable compounds of the formula H-O-(CrC6)alkyl include methanol, éthanol,or propanol. Suitable solvents include dimethylformamide or tetrahydrofuran; preferablydimethylformamide. The aforesaid reaction can be conducted at a température of about 22 °C toabout 110 °C, preferably about 85 °C. The aforesaid reaction can be conducted for a time periodof about 30 minutes to about 48 hours, preferably about 16 hours. A compound of formula Ib, whereiri A is =CR1- and R1 is -(C=O)-NH-(C1-Cs)alkyl or-(C=O)-NH-(C1-C6)alkyl-OH or -(C=O)-NH-(C1-C6)alkyl-N(CH3)2 or -(0=0)-1-(4-/V-methyipiperazine) can be prepared by reacting a compound of the formula le, wherein halogen isselected from bromo or iodo, with carbon monoxide in the presence of a palladium catalyst, abase, and a compound of the formula H2N-(Ci-C6)alkyl or H2N-(C1-C6)alkyl-OH or H2N-(C1-C6)alkyl-N(CH3)2 or /V-methylpiperazine (depending on the -(CrC^alkyl part of the desired R1) in asolvent. Suitable palladium catalysts include Pd(dppf)CI2. Suitable bases include tertiary aminebases such as triethylamine. Suitable compounds of the formulas H2N-(Ci-C6)alkyl or H2N-(CrC6)alkyl-OH or H2N-(Ci-C6)alkyl-N(CH3)2 or /V-methylpiperazine include 2-aminoethanol, N,N-dimethylethylenediamine, methylamine /V-methylpiperazine Suitable solvents includedimethylformamide or toluene; preferably dimethylformamide. The aforesaid reaction can beconducted at a température of about 22 °C to about 110 °C, preferably about 85 °C. The aforesaidreaction can be conducted for a time period of about 30 minutes to about 48 hours, preferablyabout 16 hours. 013017 46 A compound of formula le, wherein halogen is bromo or iodo, can be prepared byreacting a compound of formula Id with a suitable halogenating agent in a solvent. Suitablehalogenating agents include /V-bromosuccinimide or /V-iodosuccinimide; preferably ΛΖ-bromosuccinimide. Suitable solvents include tetrahydrofuran or dimethylformamide, preferablydimethylformamide. The aforesaid reaction can be conducted at a température of about 0 °C toabout 75 °C, preferably about 22 °C. The aforesaid reaction can be conducted for a time period ofabout 5 minutes to about 24 hours, preferably about 1 hour. A compound of formula le, wherein halogen is chloro, can be prepared by reacting acompound of formula Id with a suitable chlorinating agent in a solvent. Suitable chlorinatingagents include /V-chlorosuccinimide Suitable solvents include tetrahydrofuran ordimethylformamide; preferably dimethylformamide. The aforesaid reaction can be conducted at atempérature of about 0 °C to about 75 °C, preferably about 45 °C. The aforesaid reaction can beconducted for a time period of about 5 minutes to about 24 hours, preferably about 1 hour.

Scheme 4 refers to the préparation of a compound of the formula IVa, which is acompound of formula IV of Scheme 1, wherein A is =CH-. Referring to Scheme 4, a compound offormula IVa, wherein Lv is as described above, can be prepared by reacting a compound offormula XV, wherein Lv is as described above and each of Lv3 is a leaving group, with a suitableacid in a polar protic solvent (see Coe, J.W., Vetelino, M.G., Bradlee, M.J. Tetrahedron Lett. 1996,37, 6045-6047 incorporated herein by reference). Suitable Lv3 leaving groups include methoxy orethoxy, preferably methoxy. Suitable acids include HCl, H2SO4, para toluenesulfonic acid,camphorsulfonic acid, or Lewis acids; preferably HCl. Suitable polar protic solvents includealcohols (such as methanol or éthanol), preferably methanol. The aforesaid reaction can beconducted at a température of about 0 °C to about 100 °C, preferably about 65 °C. The aforesaidreaction can be conducted for a time period of about 5 minutes to about 24 hours, preferablyabout 1 hour. A compound of formula XV, wherein Lvand Lv3 are as described above, can be preparedby reacting a compound of formula XVI, wherein Lv and Lv3 are as described above, with areducing agent in a polar solvent. Suitable reducing agents include catalytic transfer reagentssuch as hydrazine hydrate, ammonium formate, ammonium chioride, cyclohexene, or hydrogengas in the presence of catalysts [such as Pd on carbon (see Coe, J.W., Vetelino, M.G., Bradlee,M.J. Tetrahedron Lett. 1996, 37, 6045-6047 incorporated herein by reference), Ru, Rh, Raneynickel, or Pt]; HCl or acetic acid in the presence of In, Fe, Sn, or Zn; HCI/SnCI2;SnCI2.2H2O;Bu3SnH/AIBN; or Fe3(CO)12; preferably SnCI2.2H2O or hydrogen gas in the presence of Pd oncarbon or Raney nickel. Suitable polar solvents include alcohols (such as methanol or éthanol),preferably methanol. The aforesaid reaction can be conducted at a température of about 0 °C toabout 100 °C, preferably about 23 °C. Where hydrogen gas is used the reaction pressure can be 013017 47 10 15 1 to 4 atm, preferably 1 atm. The aforesaid reaction can be conducted for a time period of about2 hours to about 48 hours, preferably about 24 hours. A compound of formula XVI, wherein Lvand Lv3 are as described above, can be preparedby reacting a compound of formula XVII, wherein Lv is as described above, with a suitable acid inan anhydrous polar protic solvent of formula Lv3-H. Suitable acids include HCl, H2SO4, or paratoluenesulfonic acid, preferably HCl. Alternative^, HCl can be generated in situ by using an HClgenerating agent such as TMS-CI or acetyl chloride, preferably TMS-CI, in an anhydrous polarprotic solvent such as methanol. Suitable anhydrous polar protic solvents of formula Lv3-H includeanhydrous alcohols (such as methanol or éthanol), preferably anhydrous methanol. The aforesaidreaction can be conducted at a température of about 23 °C to about 78 °C, preferably about 65°C. The aforesaid reaction can be conducted for a time period of about 30 minutes to about 48hours, preferably about 24 hours. A compound of formula XVII, wherein Lv is as described above, can be prepared byreacting a compound of formula XVIII, wherein Lv is as described above, with a compound offormula

20 25 30 wherein each of Lv3 is as described above, in a polar solvent. Suitable compounds of formula(CH3)2-N-CH-(Lv3)2 include dimethylformamide-dimethylacetal. Suitable polar solvents includedimethylformamide, toluene, or alcohol (such as éthanol), preferably dimethylformamide. Theaforesaid reaction can be conducted at a température of about 22 °C to about 150 °C, preferablyabout 110 °C. The aforesaid reaction can be conducted for a time period of about 15 minutes toabout 24 hours, preferably about 6 hours.

Compounds of formula (CH3)2-N-CH-(Lv3)2 are commercially available.

Compounds of the formula XVII, wherein Lv is as described above, are commercially available or alternativelÿ can be made by methods well known to those skilled in the art.

Scheme 5 refers to préparation of a compound of the formula IVb, which is a compound of formula IV of Scheme 1, wherein A is =CR1-. Referring to Scheme 5, a compound of formula IVbcan be prepared by reacting a compound of the formula XIX, wherein Lv is as described aboveand Lv4 is a leaving group, with a suitable substituted alkyne of formula M1-CHC-R1 wherein M1 is H or métal (such as Sn or B), preferably H or Sn, in the presence of a métal catalystin a polar solvent. Suitable Lv4 leaving groups include halo preferably bromo or iodo. Suitablemétal catalysts include palladium or copper catalysts (See Fagnola, M.C. et al. Tetrahedron 013017 48

Letf.1997, 38, 2307-2310 incorporated herein by référencé). Suitable polar solvents includedimethylformamide, dioxane, dimethylsulfoxide, or mixtures thereof, preferably a mixture ofdimethylformamide and dioxane. The aforesaid réaction can be conducted at a température ofabout 22 °C to about 120 °C, preferably about 90 °C. The aforesaid reaction can be conducted fora time period of about 5 minutes to about 24 hours, preferably about B hours.

Compounds of formula M1-CEC-R1 are commercially available or can be made bymethods well known to those skilled in the art. A compound of formula XIX, wherein Lvand Lv4 are as described above, can be preparedby reacting a compound of formula XX, wherein Lv and Lv4 are as described above, with areducing agent in the présence of (CH3CO)2O in a polar solvent. Suitable reducing agents includehydrogen gas in the presence of catalysts such as Pd/C (see Coe, J.W., Vetelino, M.G., Bradlee,M.J. Tetrahedron Lett.1996, 37, 6045-6047 incorporated herein by référencé), Rd, Raney nickel,or Pt; acetic acid in the presence of In, Fe, or Zn; SnCI2; or Fe3(CO)12; preferably hydrogen gas inthe presence of Pd/C; or acetic acid in the presence of Fe. Suitable polar solvents includedimethylformamide, methanol, éthanol, or acetic acid; preferably methanol or acetic acid. Theaforesaid reaction can be conducted at a température of about 20 °C to about 100 °C, preferablyabout 22 °C. Where hydrogen gas is used the reaction pressure can be 1 to 4 atm, preferably 1atm. The aforesaid réaction can be conducted for a time period of about 2 hours to about 48hours, preferably about 24 hours.

Compounds of the formula XX are commercially available or can be made by methodswell known to those skilled in the art.

Scheme 6 refers to préparation of a compound of the formula If, which is a compound offormula I of Scheme 1, wherein the group -Y-Z- has the formula -N=CH-, A is =N-, and R2 is otherthan hydrogen. Referring to Scheme 6, a compound of formula If can be prepared by reacting acompound of the formula le, which is a compound of formula I of Scheme 1, wherein the group-Y-Z- has the formula -N=CH-, A is =N-, and R2 is hydrogen, with a compound of formula R2-Lv1 wherein Lv1 is a leaving group, such as halo, preferably bromo or chloro, in the presence of asuitable base in a polar solvent. The reaction condition is as described above in the description forScheme 1 for the préparation of compounds of formula III from a compound of formula IV.

Compounds of formula le can be prepared by reacting a compound of the formula Villa,which is a compound of formula VIII of Scheme 2, wherein A is =N- and Lv is as described above,with hydrazine in a solvent. The reaction condition is as described above in the description forScheme 1 for the préparation of a compound of formula I from a compound of formula II.

Compounds of formula Villa can be prepared by reacting a compound of the formula IVa,which is a product of Scheme 4, with a nitrous acid producing agent in the presence of an acid ina solvent. Suitable nitrous acid producing agents include NaNO2, KNO2, isoamyl nitrite, or tert- 013017 49 butyl nitrite; preferably NaNO2. Suitable acids include acetic acid or aqueous HCl; preferablyacetic acid. Suitable solvents include acetic acid, benzene, dimethylformamide, toluene, oralcohols (such as methanol), preferably acetic acid. The aforesaid reaction can be conducted at atempérature of about 0 °C to about 30 °C, preferably about 0 °C warming to 23 °C. The aforesaidreaction can be conducted for a time period of about 5 minutes to about 24 hours, preferablyabout 1 hour.

Within the invention it is understood that a compound of Formula I may exhibit thephenomenon of tautomerism and that the formula drawings within this spécification represent onlyone of the possible tautomeric forms. It is to be understood that the invention encompasses anytautomeric form which modulâtes and/or inhibits kinase activity and is not to be limited merely toany one tautomeric form utilized within the formula drawings.

Some of the inventive compounds may exist as single stereoisomers (i.e., essentially freeof other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. Ailsuch single stereoisomers, racemates and mixtures thereof are intended to be within the scope ofthe présent invention. Preferably, the inventive compounds that are optically active are used inoptically pure form.

As generally understood by those skilled in the art, an optically pure compound havingone chiral center (i.e., one asymmetric carbon atom) is one that consiste essentially of one of thetwo possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound havingmore than one chiral center is one that is both diastereomerically pure and enantiomerically pure.Preferably, the compounds of the présent invention are used in a form that is at least 90%optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomericexcess (“e.e.") or diastereomeric excess (“d.e.")), more preferably at least 95% (90% e.e. or d.e.),even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98%e.e. or d.e.).

Additionally, Formula I is intended to cover solvated as well as unsolvated forms of theidentified structures. For example, Formula I include compounds of the indicated structure in bothhydrated and non-hydrated forms. Other examples of solvatés include the structures incombination with isopropanol, éthanol, methanol, DMSO, ethyl acetate, acetic acid, orethanolamine.

If the inventive compound is a base, the dêsired pharmaceutically acceptable sait may beprepared by any suitable method available in the art, for example, treatment of the free base withan inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylicacid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, suchas citric acid or tartane acid, an amino acid, such as aspartic acid or giutamic acid, an aromatic 013017 50 acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid orethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceutically acceptable sait may beprepared by any suitable method, for example, treatment of the free acid with an inorganic ororganic base, such as an amine (primary, secondary or tertiary), an alkali métal hydroxide oralkaline earth métal hydroxide, or the like. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, andtertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnésium, manganèse, iron, copper, zinc,aluminum and lithium.

In the case of agents that are soiids, it is understood by those skilled in the art that theinventive compounds and salts may exist in different crystal or polymorphie forms, ail of which areintended to be within the scope of the présent invention and specified formulas.

The pharmaceutically acceptable salts of the compound of Formula I can also exist asvarious solvatés, such as with water, methanol, éthanol, dimethylformamide, ethyl acetate and thelike. Mixtures of such solvatés can also be prepared. The source of such solvaté can be from thesolvent of crystallization, inhérent in the solvent of préparation or crystallization, or adventitious tosuch solvent.

The compound of Formula I may be used in combination with conventional antineoplasmthérapies to treat mammals, especially humans, with neoplasia. The procedures for conventionalanti-neoplasm thérapies, including chemotherapies using anti-neoplastic agents and therapeuticradiation, are readily available, and routinely practiced in the art, e.g., see Harrison's PRINCIPLESOF INTERNAL MEDICINE 11,h édition, McGraw-Hill Book Company.

Neoplasia is characterized by abnormal growth of cells which often results in the invasionof normal tissues, e. g., primary tumors or the spread to distant organs, e. g., metastasis. Thetreatment of any neoplasia by conventional non-surgical anti-neoplasm thérapies may beenhanced by the présent invention. Such neoplastic growth includes but not limited to primarytumors, primary tumors that are incompletely removed by surgical techniques, primary tumorswhich hâve been adequately treated but which are at high risk to develop a metastatic diseasesubsequently, and an established metastatic disease.

Specifically, the CHK-1 inhibitor of Formula I above may enhance the anti-neoplasmeffects of an anti-neoplastic agent. The wide variety of available anti-neoplastic agents arecontemplated for combination therapy in accordance with présent invention. In a preferredembodiment, anti-neoplastic agents that assert their cytotoxic effects by activating programmedcell death or apoptosis may be used in combination with the described CHK-1 inhibitor. The anti-neoplastic agents contemplated in accordance with the présent invention include, but are not,limited to alkylating agents, including busulfan, chlorambucil, cyclophosphamide, iphosphamide, 013017 51 melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard,triethylenemelamine, temozolomide, and SARCnu; antibiotics and plant alkaloids including actinomycin-D, bleomycin, cryptophycins,daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin,navelbine, paclitaxel, docetaxel, topotecan, Vinblastine, vincristine, VM-26, and VP-16-213;hormones and steroids including 5a-reductase inhibitor, aminoglutéthimide, anastrozole,bicalutamide, chlorotrianisene, DES, dromostanolone, estramustine, ethinyl estradiol, flutamide,fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesteroneacetate, megestrol acetate, methyl prednisolone, methyltestosterone, mitotane, nilutamide,prednisolone, SERM3, tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; synthetics includingall-trans retinoic acid, BCNU (carmustine), CBDCA carboplatin (paraplatin),CCNU (lomustine), cis-diaminedichloroplatinum (cisplatin), dacarbazine, gliadel,hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone, o, p'-DDD (lysodren, mitotane),oxaliplatin, porfimer sodium, procarbazine, GleeVec; antimetabolites includingchlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluorouracil, 5-FUDR, gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, MTA, andthioguanine; and biologics including alpha interferon, BCG, G-CSF, GM-CSF, interleukin-2,herceptin; and the like.

In a preferred embodiment of the invention, the anti-neoplastic agent is selected from thegroup consisting of alkylating agents, antibiotics and plant alkaloids, hormones and steroids,synthetic agents having anti-neoplastic activity, antimetabolites and biological molécules havinganti-neoplastic activity.

In a preferred embodiment of the invention the antineoplastic agent is selected from thegroup consisting of Ara-c, VP-16, cis-platin, adriamycin, 2-chloro-2-deoxyadenosine, 9-p-D-arabinosyl-2-fluoroadenine, carboplatin, gemcitabine, camptothecin, paclitaxel, BCNU, 5-fluorouracil, irinotecan, and doxorubicin; more preferably gemcitabine.

Ail the neoplastic conditions treatable with such anti-neoplastic agents may be treated inaccordance with the présent invention by using a combination of the compound of Formula I withone or more anti-neoplastic agents. The anti-neoplastic agents assert their cytotoxicity or anti-neoplasm effects in a variety of spécifie neoplastic conditions. For example, Ara-c is normallyused for treatment of childhood-null acute lymphoid leukemia (ALL), thymie ALL, B-cell ALL, acutemyeloid leukemia, acute granulocytic leukemia and its variants, non-Hodgkins lymphoma,myelomonocytoid leukemia, acute megakaryocytoid leukemia and Burkitt's lymphoma, Adult-B-ALL, acute myeloid leukemia, chronic lymphoid leukemia, chronic myeloid leukemia, and T cellleukemia. VP-16 is normally used for treatment of testicular carcinoma, small and large non-smallcell lung carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, choriocarcinoma, Ewing's 0 7 30 1 7 52 sarcoma, and acute granulocytic leukemia. Cis-platin can be employed for treatment of testicularcarcinome, germ cell tumors, ovarian carcinomas, prostate cancer, lung cancer, sarcomas,cervical cancer, endométrial cancer, gastric cancer, breast cancer, and cancer of the head andneck. 2-Chloro-2-deoxyadenosine and 9-P-D-arabinosyl-2-fluoroadenine can be used to treatchronic lymphoid leukemia, lymphomas and hairy cell leukemia. Doxorubicin can be used to treatacute granulocytic leukemia and its variants, ALL, breast cancer, bladder cancer, ovarian cancer,thyroid cancer, lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, sarcomas, gastriccarcinoma, prostate cancer, endométrial cancer, Wilm's tumor and neuroblastoma.

Clinical effects of anti-neoplastic agents in ail neoplastic conditions treatable withantineoplastic agents including the ones discussed above may be potentiated by use of acombination therapy with the identified CHK-1 inhibitor in accordance with the présent invention.

The CHK-1 inhibitor identified in the présent invention may also enhanpe theantineopiasm effects of radiation therapy. Usually, radiation can be used to treat the site of a solidtumor directly or administered by brachytherapy implants. The various types of therapeuticradiation which are contemplated for combination therapy in accordance with the présentinvention may be those used in the treatment of cancer which include, but are not limited to X-rays, gamma radiation, high energy électrons and High LET (Linear Energy Transfer) radiationsuch as protons, neutrons, and alpha particles. The ionizing radiation may be employed bytechniques well known to those skilled in the art. For example, X-rays and gamma rays areapplied by extemal and/or interstitial means from linear accelerators or radioactive sources. High-energy électrons may be produced by linear accelerators. High LET radiation is also applied fromradioactive sources implanted interstitially.

The spécifie dosage amount of a compound of the Formula I, a pharmaceuticallyacceptable sait, solvaté, or prodrug thereof being administered to obtain therapeutic or inhibitoryeffects may be determined in a manner known in the art according to the particular circumstancessurrounding the case, including, e.g., the spécifie agent being administered, the route ofadministration, the condition being treated, and the subject or host being treated. An exemplarytotal daily dose of a compound of the Formula I, which may be administered in single or multipledoses, contains a dosage level of from about 0.01mg/kg body weight to about 50 mg/kg bodyweight.

The compounds of the Formula I of the invention may be administered by any of a varietyof suitable routes, such as orally, rectally, transdermally, subcutaneously, intravenously,intramuscularly, or intranasally. The compounds of the Formula I are preferably formulated intocompositions suitable for the desired routes before being administered. A pharmaceutical composition or préparation according to the invention comprises aneffective amount of a compound of the Formula I, optionally one or more other active agents, anda pharmaceutically acceptable carrier, such as a diluent or excipient for the agent; when the 013017 53 carrier serves as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle,excipient, or medium for the active ingredient(s). Compositions according to the invention may bemade by admixing the active ingredient(s) with a carrier, or diluting it with a carrier, or enclosing orencapsulating it within a carrier, which may be in the form of a capsule, sachet, paper container,or the like. Exemplary ingrédients, in addition to one or more compounds of the Formula I andany other active ingrédients, include Avicel (microcrystalline cellulose), starch, lactose, calciumsulfate dihydrate, terra alba, sucrosè, talc, gelatin, agar, pectin, acacia, magnésium stéarate,stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethylene gfycol, propylene glycol, sorbitan monostearate,polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate,disodium hydrogen phosphate, sodium chloride, and water.

The compositions may be prepared in any of a variety of forms suitable for the desiredmode of administration. For example, pharmaceutical compositions may be prepared in the formof tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions,syrups, aérosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weightof acompound of the Formula I), soft-gel and hard-gel capsules, suppositories, stérile injectablesolutions, stérile packaged powders, and the like.

Similarly, the carrier or diluent may include time-delay or time-release material known inthe art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like. A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, thepréparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in theform of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about25 mg to about 1 g. If a liquid carrier is used, the préparation can be in the form of syrup,émulsion, soft gelatin capsute, stérile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaqeutically acceptable sait of aninventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3Msolution of succinic acid or citric acid. If a soluble sait form is not avaiiable, the agent may bedissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolventsinclude, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the total volume. A compound ofFormula I may be dissolved in DMSO and diluted with water. The composition may also be in theform of a solution of a sait form of the active ingrédient in an appropriate aqueous vehicle such aswater or isotonie saline or dextrose solution.

The compositions of the invention may be manufactured in manners generally known forpreparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, 013017 54 dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in a conventionai manner using oneor more physiologically acceptable carriers, which may be selected from excipients and auxiliarïesthat facilitate processing of the active compounds into préparations which can be usedpharmaceutically.

Proper formulation is dépendent upon the route of administration chosen. For injection,the agents of the invention may be formulated into aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, pénétrants appropriate to the barrier to be permeated are used inthe formulation. Such pénétrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the activecompounds with pharmaceutically acceptable carriers known in the art. Such carriers enable thecompounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.Pharmaceutical préparations for oral use can be obtained using a solid excipient in admixture withthe active ingrédient (agent), optionally grinding the resulting mixture, and processing the mixtureof granules after adding suitable auxiliarïes, if desired, to obtain tablets or dragee cores. Suitableexcipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; andcellulose préparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin,gum, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, methyl cellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinkedpolyvinyl pyrrolidone, agar, or alginic acid or a sait thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugarsolutions may be used, which may optionally contain gum arable, polyvinyl pyrrolidone, Càrbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solventsor solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of active agents.

Pharmaceutical préparations which can be used orally include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingrédients in admixture with fillers such aslactose, binders such as starches, and/or lubricants such as talc or magnésium stéarate, and,optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended insuitable liquids, such as fatty oils, liquid paraffïn, or liquid polyethylene glycols. In addition,stabilizers may be added. Ail formulations for oral administration should be in dosages suitablefor such administration. For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventionai manner. 013017 55

For administration intranasally or by inhalation, the compounds for use according to theprésent invention are conveniently deiivered in the form of an aérosol spray présentation frompressurized packs or a nebulizer, with the use of a suîtable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suîtable gas. In the case of a pressurized aérosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in aninhaler or insufflator and the like may be formulated containing a powder mix of the compoundand a suîtable powder base such as lactose or starch.

The compounds may be formulated for parentéral administration by injection, e.g., bybolus injection or continuous infusion. Formulations for injection may be presented in unit-dosageform, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or émulsions in ôily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parentéral administration include aqueous solutions ofthe active compounds in water-soluble form. Additionally, suspensions of the active agents maybe prepared as appropriate oily injection suspensions. Suîtable lipophilie solvents or vehiclesinclude fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycérides, or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordëxtran. Optionally, the suspension may also contain suîtable stabilizers or agents which increasethe solubility of the compounds to allow for the préparation of highly concentrated solutions.

For administration to the eye, the active agent is deiivered in a pharmaceuticallyacceptable ophthalmic vehicle such that the compound is maintained in contact with the ocularsurface for a sufficient time period to allow the compound to penetrate the comeal and internairégions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body,aqueous humor, vitreous humor, cornea, iris/ciiiary, lens, choroid/retina and sciera. Thepharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or anencapsulating material. A compound of the invention may also be injected directly into thevitreous and aqueous humor.

Alternatively, the active ingrédient may be in powder form for constitution with a suîtablevehicle, e.g., stérile pyrogen-free water, before use. The compounds may also be formulated inrectal compositions such as suppositories or rétention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

The compounds may also be formulated as a depot préparation. Such long-actingformulations may be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, the compounds may beformulated with suîtable polymeric or hydrophobie materials (for example, as an émulsion in an 0130Π 56 acceptable oil) or ion-exchange resins, or as sparingly soluble dérivatives, for example, as asparingly soluble sait. A pharmaceutical carrier for hydrophobie compounds is a cosolvent System comprisingbenzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.The cosolvent system may be a VPD co-solvent System. VPD is a solution of 3% w/v benzylalcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300,made up to volume in absolute éthanol. The VPD co-solvent system (VPD:5W) contains VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobiecompounds well, and itself produces low toxicity upon systemic administration. Naturally, theproportions of a co-solvent system may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: forexample, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; thefraction size of polyethylene glycol may be varied; other biocompatible polymère may replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may besubstituted for dextrose.

Altematively, other delivery Systems for hydrophobie pharmaceutical compounds may beemployed. Liposomes and émulsions are known examples of delivery vehicles or carriers forhydrophobie drugs. Certain organic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, the compounds may be deliveredusing a sustained-release system, such as semipermeable matrices of solid hydrophobiepolymère containing the therapeutic agent. Various sustained-release materials hâve beenestablished and are known by those skilled in the art. Sustained-release capsules may,depending on their Chemical nature, release the compounds for a few weeks up to over 100 days.Depending on the Chemical nature and the biological stability of the therapeutic reagent, additionalstrategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriersor excipients. Examples of such carriers or excipients include calcium carbonate, calciumphosphate, sugars, starches, cellulose dérivatives, gelatin, and polymère such as polyethyleneglycols.

Some of the compounds of the invention may be provided as salts with pharmaceuticallycompatible counter ions. Pharmaceutically compatible salts may be formed with many acids,including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the corresponding free-base forms.

The compounds of the Formula I, a pharmaceutically acceptable sait, solvaté, orprodrug thereof are useful as anti-angiogenesis agents and as agents for modulating and/orinhibiting the activity of protein kinases, thus providing treatments for cancer or other diseasesassociated with cellular prolifération mediated by protein kinases. 013017 57

Therapeutically effective amounts of the agents of the invention may be used to treatdiseases mediated by modulation or régulation of protein kinases. An "effective amount” isintended to mean that amount of an agent that, when administered to a mammal in need of suchtreatment, is sufficient to effect treatment for a disease mediated by the activity of one or more 5 kinases. Thus, e.g., a therapeutically effective amount of a compound of the Formula I, apharmaceutically acceptable sait, solvaté, or prodrug thereof is a quantity sufficient to modulate,regulate, or inhibit the activity of one or more kinases such that a disease condition which ismediated by that activity is reduced or alleviated. BIOCHEMICAL AND BIOLQGICAL EVALUATION10 Enzyme Assavs CHK-1 Construct for Assav

As previously detailed in European Patent Application No. 1 096 014 A2 (filed October 31,2000), the C-terminally His-tagged kinase domain of human CHK-1 (KH289), amino acid residues1-289, can be expressed using the baculovirus/insect cell System. This construct has been shown 15 to possess catalytic activity approximately 10-fold greater than full length CHK-1. The Bac-to-BacSystem (Life Technologies) can be used to generate recombinant baculovirus for the expressionof KH289 as per instructions. Recombinant viruses can be confirmed by PCR for the presence ofCHK-1 cDNA insertion. Protein expression can be confirmed by SDS-PAGE or Western blot withCHK-1 polyclonal antibodies. Sf9 insect cells (Invitrogen, Carlsbad, CA, USA) can be used for 20 initial amplification of recombinant virus stock. High titer stocks of recombinant viruses can begenerated by 2 to 3 rounds of amplification using Sf21 insect cells. Hi-S insect cells (Invitrogen,Carlsbad, CA, USA) can be used for protein production. Both Sf9 and Hi-S cell lines can beadapted to grow in insect medium containing 1% Fêtai Bovine Sérum (Life Technologies, GrandIsland, NY, USA). The viral stock was stored at 10°C and used for large-scale protein production 25 within 2 months to avoid viral instability. For protein production, infected Hi-S cells can beharvested by centrifugation and stored at -80°C. From these cells, 6X-His tagged KH289(identified by SDS-PAGE) can be obtained after purification and can be fiash-frozen in liquid N2and stored at -80°C. Maintaining sait concentration around 500 mM NaCI including 5% glycerolwas found to be crucial for preventing aggregation of CHK-1 proteins during purification _and 30 storage. CHK-1 Assav

As previously detailed in European Patent Application No. 1 096 014 A2 (filed October 31,2000), the enzymatic activity of a kinase can be measured by its ability to catalyze the transfer of aphosphate residue from a nucleoside triphosphate to an amino acid side chain in a selected 35 protein target. The conversion of ATP to ADP generally accompanies the catalytic reaction.Herein, a synthetic substrate peptide, Syntide-2, having amino acid sequencePLARTLSVAGLPGKK can be utilized. The production of ADP from ATP that accompanies 013017 58 phosphoryl transfer to the substrate can be coupled to oxidation of NADH usingphosphoenolpyruvate (PEP) through the actions of pyruvate kinase (PK) and lacticdehydrogenase (LDH). The oxidation of NADH can be monitored by following the decrease ofabsorbance at 340 nm (e340=6.22 cm-1 mM-1) using a HP8452 spectrophotometer. Typicalreaction solutions contained: 4 mM PEP, 0.15 mM NADH, 28 units of LDH/mL, 16 units of PK/mL,3 mM DTT, 0. 125 mM Syntide-2, 0.15 mM ATP and 25 mM MgC)2 in 50 mM TRIS pH 7.5;-400mM NaCI. Assays can be initiated with 10 nM of kinase domain of CHK-1, KH289. Ki values canbe determined by measuring initial enzyme activity in the presence of varying concentrations ofinhibitors. The data can be analyzed using Enzyme Kinetic and Kaleidagraph software. VEGF-R2 Construct for Assay

This construct détermines the ability of a test compound to inhibit tyrosine kinase activity.A construct (VEGF-R2A50) of the cytosolic domain of (human) vascular endothélial growth factorreceptor 2 (VEGF-R2) lacking the 50 central residues of the 68 residues of the kinase insertdomain can be expressed in a baculovirus/insect cell System. Of the 1356 residues of full-lengthVEGF-R2, VEGF-R2A50 contains residues 806-939 and 990-1171, and also one point mutation(E990V) within the kinase insert domain relative to wild-type VEGF-R2. Autophosphorylation ofthe purified construct can be performed by incubation of the enzyme at a concentration of 4 μΜ inthe presence of 3 mM ATP and 40 mM MgCI2 in 100 mM HEPES, pH 7.5, containing 5% glyceroland 5 mM DTT, at 4 °C for 2 hours. After autophosphorylation, this construct has been shown topossess catalytic activity essentially équivalent to the wild-type autophosphorylated kinase domainconstruct. See Parast et al. (1998) Biochemistry 37:16788-16801. VEGF-R2 Assav

Coupled Spectrophotometric fFLVK-P) Assay

The production of ADP from ATP that accompanies phosphoryl transfer can be coupledto oxidation of NADH using phosphoenolpyruvate (PEP) and a System having pyruvate kinase(PK) and lactic dehydrogenase (LDH). The oxidation of NADH can be monitored by following thedecrease of absorbance at 340 nm (e^o = 6.22 cm'1 mM'1) using a Beckman DU 650spectrophotometer. Assay conditions for phosphorylated VEGF-R2A50 can be the following: 1mM PEP; 250 μΜ NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mM poly(E4Y,); 1 mM ATP; and 25 mM MgCI2 in 200 mM HEPES, pH 7.5. Assay conditions for unphosphorylatedVEGF-R2A50 can be the following: 1 mM PEP; 250 μΜ NADH; 50 units of LDH/mL; 20 units ofPK/mL; 5 mM DTT; 20 mM poly(E4Y1); 3 mM ATP; and 60 mM MgCI2 and 2 mM MnCI2 in 200 mMHEPES, pH 7.5. Assays can be initiated with 5 to 40 nM of enzyme. Enzyme percentageinhibition values can be determined by measuring enzyme activity in the presence of Ο.ΟδμΜ testcompound. The data can beanalyzed using Enzyme Kinetic and Kaleidagraph software.

FGFR FGF-R1 Construct for Assav 013017 59

The intracellular kinase domain of (human) FGF-R1 can be expressed using thebaculovirus vector expression system starting from the endogenous méthionine residue 456 toglutamate 766, according to the residue numbering system of Mohammadi et al. (1996) Mol. Cell.Biol. 16:977-989. In addition, the construct also has the following 3 amino acid substitutions:L457V, C488A, and C584S. FGF-R Assay

The spectrophotometric assay can be carried out as described above for VEGF-R2,except for the following changes in concentration: FGF-R = 50 nM, ATP = 2 mM, and poly(E4Y1)= 15 mM. K| values can be determined by measuring enzyme activity in the presence of varyingconcentrations of test compounds.

PHK

Phosohorvlase Kinase Construct for Assay.

The truncated catalytic subunit (gamma subunit) of phosphorylase kinase (amino acids 1-298) can be expressed in E.coli and isolated from inclusion bodies. Phosphorylase kinase canthen be refolded and stored in glycerol at -20 °C.

Phosphorylase Kinase Assay.

In the assay, the purified catalytic subunit can be used to phosphorylate phosphorylase busing radiolabled ATP. Briefly, 1.5 mg/ml of phosphorylase b can be incubated with 10 nMphosphorylase kinase in 10 mM MgCI2, 50 mM Hepes pH 7.4, at 37 °C. The reaction can bestarted with the addition of ATP to 100 uM and incubated for 15 min at 25 °C or 37 °C. Thereaction can be terminated and proteins can be precipitated by the addition of TCA to 10% finalconcentration. The precipitated proteins can be isolated on a 96 well Millipore MADP NOB filterplate. The filter plate can be extensively washed with 20% TCA, and dried. Scintilation fluid canbe then added to the plate and incorporated radiolabel can be counted on a Wallac microbetacounter. The % inhibition of phosphoryl transfer from ATP to phosphorylase b in the presence of10 μΜ of compound can then be measured. CHK-2 Assav CHK-2 enzyme can be obtained from Upstate Group, Inc. and is an N-terminal, GST-tagged and C-terminal His-tagged fusion protein corresponding to amino acids 5-543 of humanCHK-2 as confirmed by mass tryptic fingerprinting, expressed in E. coii; Mr~87kDa. The assaycondition for CHK-2 can be as described above for CHK-1, except that the enzyme CHK2(0.059μΜ) can be utilized in place of KH289. Further, no NaCI can be added. CDK-1 Assav CDK-1/cyclin B, active complex can be obtained from Upstate Group, Inc. and is a C-terminal, His-tagged CDK-1 and an N-terminal GST-tagged-cyclin B as confirmed by mass trypticfingerprinting and protein sequencing, produced individually in Sf21 cells and then complexed invitro. The assay condition for CDK-1 can be as described above for CHK-1, except that the 0130Π 60 enzyme complex CDK-1/cyclin B (0.2μΜ) can be utilized in place of KH289, and Histone-H1(Upstate USA, Inc.) (0.059μΜ) can be utilized as a substrate in place of Syntide-2. Further, noNaCI can be added. WEE-1 assav Déifia tR) Assav Protocol for WEE-1 WEE-1 enzyme can be obtained from Upstate Group, Inc. and is an N-terminal, GST-tagged fusion protein to full length rat WEE-1, expressed in E. coli; Mr~100kDa. This kinaseassay can be carried out on coated poly (Glu-Tyr) 4:1 (random copolymer) 96-well filter plates(NoAb Diagnostics). The assay volume can be 10ΟμΙ per well plus 2μΙ DMSO (contrai) or 2μΙ ofcompound in DMSO. Buffer A can be 10% glycerol, 20mM TRIS (pH7.5), 10mM MgCI2, 50mMNaCI and 5mM DTT. The plates can be prepared by automation.

To an appropriate well can be added either 2μΙ of DMSO (contrai) or 2μΙ of compound inDMSO. To the positive contrai wells can be added 30μΙ of 0.5M EDTA. To each well can be added50μΙ ATP in Buffer A such that the ATP assay concentration can be 33μΜ. To start the reaction,50μΙ Wee1 in Buffer A can be added to each well such that the Wee1 assay concentration can beO.lng/μΙ. The plate can be can be mixed by shaking and then allowed to remain at roomtempérature for 30 minutes. To stop the reaction, the plate can be washed once with Déifia Washon an EL405 plate washer. To each well can be added 100μΙ of Eu P Y in Delfia(R) assay buffersuch that the EuPY assay concentration can be 0.0149 ng/μΙ. The plate can be allowed to sit for 1hours or ovemight. The plate can be washed once again with Delfia<R) Wash (EL405 platewasher), and allowed to dry. To each well can be added 100μΙ of Déifia (R) Enhancement solutionand the plate can be allowed to sit for 10 minutes. The plate can be read on Wallac's Victorfluorescence reader (Europium Protocol). Kj values can be determined by measuring enzymeactivity in the presence of varying concentrations of test compounds. SGK Assav SGK (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 8mM MOPS pH7.0, 0.2mM EDTA 30μΜ Crosstide, 10mM MgAcetate and [γ-33Ρ-ΑΤΡ](Spécifie activity approximately 500cpm/pmol, concentration as required) to form a final reactionvolume of 25μΙ. Compounds can be tested at 1μΜ. The réaction can be initiated by the addition ofMgz+ [γ-33Ρ-ΑΤΡ]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at roomtempérature, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution.10μΙ of the reaction can then be spotted onto a P30 filtermat and washed three times for 5minutes in 50mM phosphoric acid and once in methanol prior to drying and scintillation counting.Résulte represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in contrai incubations without test compounds. AM P K Assav 013017 61 AMPK (rat) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubated with50mM Hepes pH7.4, 1mM DTT, 0.02% Brij35, 200μΜ AMP, 200μΜ AMARAASAAALARRR,10mM MgAcetate and [y-33P-ATP] (Spécifie activity approximately 500cpm/pmol, concentration asrequired) to form a final reaction volume of 25μΙ. Compounds can be tested at 1μΜ. The reactioncan be inltiated by the addition of Mg2+ [y-33P-ATP], The ATP concentration can be 10μΜ. Afterincubation for 40 minutes at room température, the reaction can be stopped by the addition of 5μΙof a 3% phosphoric acid solution. 10μΙ of the reaction can then be spotted onto a P30 filtermat andwashed three fîmes for 5 minutes in 75mM phosphoric acid and once in methanol prior to dryingand scintillation counting. Results represent an average of two experiments and enzymatic activitycan be expressed as a percentage of that in contrai incubations without test compound. LCK Assav LCK (human) (Upstate Group, inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 50mM Tris pH7.5, 0.1mM EGTA, 0.1mM NaVanadate, 250DM KVEKIGEGTYGWYK (CDC2peptide), 10mM MgAcetate and [y33P-ATP] (Spécifie activity approximately 500cpm/pmol,concentration as required) to form a final reaction volume of 25μΙ. Compounds can be tested at1μΜ. The reaction can be initiated by the addition of Mg2+ [y33P-ATPJ. The ATP concentration canbe 10μΜ. After incubation for 40 minutes at room température, the reaction can be stopped by theaddition of 5μΙ of a 3% phosphoric acid solution. 10μΙ of the reaction can then be spotted onto aP30 filtermat and washed three times for 5 minutes in 75mM phosphoric acid and once inmethanol prior to drying and scintillation counting. Results represent an average of twoexperiments and enzymatic activity can be expressed as a percentage of that in contraiincubations without test compound. MAPK2 Assav MAPK2 (mouse) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 25mM Tris pH 7.5, 0.02mM EGTA, 0.33mg/ml myelin basic protein, 10mM MgAcetate and [y-“P-ATP] (Spécifie activity approximately 500cpm/pmol, concentration as required) to form a finalreaction volume of 25μΙ. Compounds can be tested at 1μΜ. The réaction can be initiated by theaddition of Mg2+ [y-33P-ATP], The ATP concentration can be 10μΜ. After incubation for 40 minutesat room température, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acidsolution. 10μΙ of the réaction can then be spotted onto a P30 filtermat and washed three times for5 minutes in 75mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in contrai incubations without test compound. MSK1 Assav MSK1 (human) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 8mM MOPS pH7.0, 0.2mM EDTA, 30pM Crosstide, 10mM MgAcetate and [y-33P-ATP] 013017 62 (Spécifie activity approximately 500cpm/pmol, concentration as required) to form a final reactionvolume of 25μΙ. Compounds can be tested at 1μΜ. The reaction can be initiated by the addition ofMg2+ [γ-33Ρ-ΑΤΡ]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at roomtempérature, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution.10μΙ of the reaction can then be spotted onto a P30 filtermat and washed three times for 5minutes in 50mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in contrai incubations without test compound. PKBa Assav PKBa (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 8mM MOPS pH7.0, 0.2mM EDTA, 30μΜ Crosstide, 10mM MgAcetate and [γ-^Ρ-ΑΤΡ](Spécifie activity approximately 500cpm/pmol, concentration as required) to form a final reactionvolume of 25μΙ. Compounds can be tested at 1μΜ. The reaction can be initiated by the addition ofMg2+ [γ-^Ρ-ΑΤΡ]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at roomtempérature, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution.10μΙ of the réaction can then be spotted onto a P30 filtermat and washed three times for 5minutes in 50mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in contrai incubations without test compound. ROCKII Assav ROCKII (rat) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 50mM Tris pH7.5, 0.1mM EGTA, 30DM KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK,10mM MgAcetate and [ψ-33Ρ-ΑΤΡ] (Spécifie activity approximately 500cpm/pmol, concentrationas required) to form a final reaction volume of 25μΙ. Compounds can be tested at 1μΜ. Thereaction can be initiated by the addition of Mg2+ (γ-33Ρ-ΑΤΡ). The ATP concentration can be 10μΜ.After incubation for 40 minutes at room température, the reaction can be stopped by the additionof 5μΙ of a 3% phosphoric acid solution. 10μΙ of the reaction can then be spotted onto a P30filtermat and washed three times for 5 minutes in 75mM phosphoric acid and once in methanolprior to drying and scintillation counting. Results represent an average of two experiments andenzymatic activity can be expressed as a percentage of that in control incubations without testcompound. d70 S6K Assav p70S6K (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 8mM MOPS pH7.0, 0.2mM EDTA, 100μΜ KKRNRTLTV, 10mM MgAcetate and [γ-33Ρ-ΑΤΡ](Spécifie activity approximately 500cpm/pmol, concentration as required) to form a final reactionvolume of 25μΙ. Compounds can be tested at 1 μΜ. The reaction can be initiated by the addition of

ST us i ,r? 5 /; 63

Mg2+ [y-33P-ATP], The ATP concentration can be 10μΜ. After incubation for 40 minutes at roomtempérature, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution.10μΙ of the reaction can then be spotted onto a P30 filtermat and washed three times for 5minutes in 75mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in control incubations without test compound. PKA Assav PKA (bovine) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 8mM MOPS pH7.0, 0.2mM EDTA, 30μΜ LRRASLG (Kemptide), 10mM MgAcetate and [y-33P-ATP] (Spécifie activity approximately 500cpm/pmol, concentration as required) to form a finalreaction volume of 25μΙ. Compounds can be tested at 1μΜ. The reaction can be initiated by theaddition of Mg2+ [y-33P-ATP], The ATP concentration can be 10μΜ. After incubation for 40 minutesat room température,, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acidsolution. 1ΟμΙ of the reaction can then be spotted onto a P30 filtermat and washed three times for5 minutes in 50mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in control incubations without test compound. MAPK1 Assav MAPK1 (human) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 25mM Tris pH7.5, 0.02mM EGTA, 1mM synthetic peptide, 10mM MgAcetate and [y-æP-ATP](Spécifie activity approximately 500cpm/pmol, concentration as required) to form a final reactionvolume of 25μΙ. Compounds can be tested at 1μΜ. The reaction can be initiated by the addition ofMg2+ fy-33P-ATP]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at roomtempérature, the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution.10μΙ of the reaction can then be spotted onto a P30 filtermat and washed three times for 5minutes in 75mM phosphoric acid and once in methanol prior to drying and scintillation counting.Results represent an average of two experiments and enzymatic activity can be expressed as apercentage of that in control incubations without test compound. cSRC Assav cSRC (human) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedWith 8mM MOPS pH7.0, 0.2mM EDTA, 250μΜ KVEKIGEGTYGWYK (CDC2 peptide), 10mMMgAcetate and [y-33P-ATP] (Spécifie activity approximately 500cpm/pmol, concentration asrequired) to form a final réaction volume of 25μΙ. Compounds can be tested at 1μΜ. The reactioncan be initiated by the addition of Mg2+ [y-33P-ATP]. The ATP concentration can be 10μΜ. Afterincubation for 40 minutes at room température, the réaction can be stopped by the addition of 5μΙof a 3% phosphoric acid solution, 10μΙ of the reaction can then be spotted onto a P30 filtermat and 013017 64 washed three times for 5 minutes in 75mM phosphoric acid and once in methanol prior to dryingand scintillation counting. Results represent an average of two experiments and enzymatic activitycan be expressed as a percentage of that in control incubations without test compound. PRK2 Assav 5 PRK2 (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubated with 50mM Tris pH7.5, 0.1 mM EGTA, 0.1% β-mercaptoethanol, 30μΜ AKRRRLSSLRA, 10mMMgAcetate and [γ-33Ρ-ΑΤΡ] (Spécifie activity approximately 500cpm/pmol, concentration asrequired) to form a final reaction volume of 25μΙ. Compounds can be tested at 1μΜ. The reactioncan be initiated by the addition of Mg2+ [γ-33Ρ-ΑΤΡ], The ATP concentration can be 10μΜ. After 10 incubation for 40 minutes at room température, the reaction can be stopped by the addition of 5μΙof a 3% phosphoric acid solution. 10μΙ of the reaction can then be spotted onto a P30 filtermat andwashed three times for 5 minutes in 75mM phosphoric acid and once in methanol prior to dryingand scintillation counting. Results represent an average of two experiments and enzymatic activitycan be expressed as a percentage of that in control incubations without test compound. 15 PDK1 Assav PDK1 (human) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubated with 50mM Tris pH7.5, 100μΜ KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC(PDKtide), 0.1% β-mercaptoethanol, 10mM MgAcetate and [γ-33Ρ-ΑΤΡ] (Spécifie activityapproximately 500cpm/pmol, concentration as required) to form a final reaction volume of 25μΙ. 20 Compounds can be tested at 1μΜ. The reaction can be initiated by the addition of Mg2+ [γ-^Ρ-ATP], The ATP concentration can be 10μΜ. After incubation for 40 minutes at room température,the reaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution. 10μΙ of thereaction can then be spotted onto a P30 filtermat and washed three times for 5 minutes in 75mMphosphoric acid and once in methanol prior to drying and scintillation counting. Results represent 25 an average of two experiments and enzymatic activity can be expressed as a percentage of thatin control incubations without test compound. FYN Assav FYN (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 50mM Tris pH7.5, 0.1 mM EGTA, 0.1 mM NaVanadate, 250μΜ KVEKIOEGTYGWYK (CDC2 30 peptide), 10mM MgAcetate and [γ-33Ρ-ΑΤΡ] (Spécifie activity approximately 500cpm/pmol,concentration as required) to form a final réaction volume of 25μΙ. Compounds can be tested at1μΜ. The reaction can be initiated by the addition of Mg2+ [y-33P-ATP]. The ATP concentration canbe 10μΜ. After incubation for 40 minutes at room température, the reaction can be stopped by theaddition of 5μΙ of a 3% phosphoric acid solution. 10μΙ of the reaction can then be spotted onto a 35 P30 filtermat and washed three times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying and scintillation counting. Results represent an average of two 013017 65 experiments and enzymatic activity can be expressed as a percentage of that in contraiincubations without test compound. PKCpll (human) (Upstate Group, Inc., KINASEPROFILER™) (5-1 OmU) can be incubatedwith 20mM Hepes pH7.4, 0.03% Triton X-100, 0.1mM CaCI2, 0.1mg/ml phosphatidylserine,10pg/ml diacylglycérol, 0.1mg/ml histone H1, 10mM MgAcetate and [y-33P-ATP] (Spécifie activityapproximately 500cpm/pmol, concentration as required) to form a final reaction volume of 25μΙ.Compounds can be tested at 1μΜ. The reaction can be initiated by the addition of Mg2+ [γ-33Ρ-ATP]]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at room température,the réaction can be stopped by the addition of 5μΙ of a 3% phosphoric acid solution. 10μΙ of thereaction can then be spotted onto a P30 filtermat and washed three times for 5 minutes in 75mMphosphoric acid and once in methanol prior to drying and scintillation counting. Results representan average of two experiments and enzymatic activity can be expressed as a percentage of thatin control incubations without test compound. PKCy Assav PKCy (human) (Upstate Group, Inc., KINASEPROFILER™) (5-10mU) can be incubatedwith 20mM Hepes pH7.4, 0.03% Triton X-100, 0.1 mM CaCb, 0.1mg/ml phosphatidylserine,10pg/ml diacylglycérol, 0.1mg/ml histone H1, 10mM MgAcetate and [y-33P-ATP] (Spécifie activityapproximately 500cpm/pmol, concentration as required) to form a final reaction volume of 25μΙ.Compounds can be tested at 1μΜ. The reaction can be initiated by the addition of Mg2+[y-33P-ATP]. The ATP concentration can be 10μΜ. After incubation for 40 minutes at room température,the reaction can be stopped by the addition of 5yl of a 3% phosphoric acid solution. 10μΙ of thereaction can then be spotted onto a P30 filtermat and washed three times for 5 minutes in 75mMphosphoric acid and once in methanol prior to drying and scintillation counting. Results representan average of two experiments and enzymatic activity can be expressed as a percentage of thatin control incubations without test compound.

Whole Cell Checkpoint Abrogation Assav

Chk1 Mitotic Index ELISA Assav

To examine the in vitro effects of Chk1 inhibitory compounds, an ELISA assay can bedesigned to monitor the abrogation of DNA damage-induced checkpoint control. The assay canbe based on the trapping and détection of mitotic cells following DNA damage-induced arrestPhosphorylation of Histone H3 on serine 10 has been shown to correlate with mitosis andtherefore can be required for chromosome condensation; consequently a mitosis spécifiepho5pho-epitope on Histone H3 can be used as a signal for checkpoint abrogation. CA-46 (lymphoma) cells can be treated with a DNA damaging agent, such ascamptothecin (Sigma), at 50nM for 8 hours to induce DNA damage. The control compound orChk1 inhibitor can be then added at increasing concentrations with Nocodazole (Sigma) at 013017 66 0.1 pg/ml and.plates can be incubated for 16 hours. Control cells, where oniy Chk1 inhibitors canbe added, can be prepared as well to assure that the inhibitors alone hâve no effect on the cellcycle. The cells can be then harvested, washed with PBS, and crude acid extraction can beperformed. Pellets can be resuspended in 80gl of Acid Extraction Buffer (10mM Hepes pH 7.9,1.5mM MgCI2, 10mM KCI, 0.5mM DTT, 1.5mM PMSF, 0.4N sulfuric acid), vortexed briefly, andincubated for 30 minutes on ice. Samples can be then centrifuged and 75μΙ of the supernatantcan be transferred to a 96 well flat-bottom plate (VWR 3596). Next 15μΙ Neutralizing Cocktail (#of samples x (10μΙ 10N NaOH + 5μΙ 1M Tris Base) can be added to each well, and after mixing,5μΙ of this can be transferred to another 96 well plate with 100μΙ 50mM Tris base (pH 9.6) in eachwell. Samples can be dried overnight. The wells can be then washed with 200μΙ ELISA washbuffer (PBS with 20mM Tris pH 7.5, 0.05% Tween 20) 5 times and blocked with 200μΙ blockingbuffer (PBS with 20mM Tris pH 7.5, 0.05% Tween 20, 3.5% Dry milk, 1.5% BSA. pH to 7.5 afterpréparation) for 1 hour at room température. Following wash and block, anti-phospho Histone H3antibodies (Upstate USA, Inc., rabbit polyclonal) can be added at 0.5pg/ml in block (100μΙ perwell) and incubated for 2 hours at room température. Wells can be washed again to removeunbound primary antibody and 100μΙ alkaline phosphatase conjugated secondary antibodies at0.3mg/ml (Pierce, goat anti-rabbit IgG (HOURS+L)) in block can be added for 1 hour at roomtemp. Wells can be washed 5 times to remove unbound secondary antibody, and washed again 3times with PBS alone to remove détergents. Then 100μΙ alkaline phosphatase substrate (Pierce1-Step pNPP) can be added to wells. Plates can be protected from light and incubated at roomtemp for 1 hour. The OD can be read on Molecular Devices Vmax Kinetic Microplate Reader at405nm. The ratio of the OD (optical density) of a compound treated sample to the Nocodazoleonly treated sample (about 100% mitotic or abrogation) can be expressed in a percentage, andquantifies the percent abrogation of the checkpoint. The concentration at which a compoundcauses 50% abrogation of the checkpoint can be called the EC50. The raw OD values can begraphed in Excel, and an ECS0 value can be generated using Kaleidograph software. Strong signalresults from Nocodazole only treated cells, and equals 100% mitosis in this assay. Camptothecin+ Nocodazole treated control samples hâve low signal, signifying no mitosis and therefore, nocheckpoint abrogation. When potent Chk1 inhibitors are added to Camptothecin treated cells withNocodazole, a high signal can be generated (generally in a dose dépendent manner), due to thecheckpoint abrogation activity caused by the combination treatment.

The examples above illustrate compounds according to Formula I and assays that mayreadily be performed to détermine their activity levels against the various kinase complexes. It willbe apparent that such assays or other suitable assays known in the art may be used to select aninhibitor having a desired level of activity against a selected target. 67

The exemplary compounds described above may be formulated into pharmaceuticalcompositions according to the following general examples.

Parentéral Composition

To préparé a parentéral pharmaceutical composition suitable for administration byinjection, 100 mg of a water-soluble sait of a compound of Formula I or II may be dissolved inDMSO and then mixed with 10 mL of 0.9% stérile saline. The mixture may be incorporated into adosage unit form suitable for administration by injection.

Oral Composition

To préparé a pharmaceutical composition for oral delivery, 100 mg of a compound ofFormula I or II may be mixed with 750 mg of lactose. The mixture may be incorporated into anoral dosage unit for, such as a hard gelatin capsule, which may be suitable for oral administration.

The starting materials used in the examples are commercially available and/or can beprepared by techniques known in the art. Freebases and salts of prepared starting materials andintermediates were used interchangeably and are indicated. Freebases were prepared by additionof a tertiary base to the sait followed by silica gel chromatograpy of the resulting freebase ifnecessary. Salts were prepared by adding an équivalent amount of the appropriate acid to thefreebase in a slurry or solution.

The préparation of spécifie preferred compounds of the invention is described in detail inthe following examples. The artisan will recognize that the Chemical reactions described may bereadily adapted to préparé a number of other kinase inhibitors of the invention. For example, thesynthesis of non-exemplified compounds according to the invention may be successfullyperformed by modifications apparent to those skilled in the art, e.g., by appropriately protectinginterfering groups, by changing to other suitable reagents known in the art, or by making routinemodifications of reaction conditions. Alternatively, other reactions disclosed herein or known inthe arf will be recognized as having applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated ail températures are setforth in degrees Celsius and ali parts and percentages are by weight. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. andwere used without further purification unless otherwise indicated. Tetrahydrofuran (THF) distilledfrom calcium hydride and N, N-dimethylformamide (DMF) were purchased from Aldrich in Sureseal bottles and used as received. Ail solvents were purified using standard methods readilyknown to those skilled in the art, unless otherwise indicated.

The réactions set forth below were done generally under a positive pressure of argon orwith a drying tube, at ambient température (unless otherwise stated), in anhydrous solvents, andthe reaction flasks were fitted with rubber septa for the introduction of substrates and reagents viasyringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC)was performed on glass-backed silica gel 60 F 254 plates Analtech (0.25 mm) and eluted with the 013017 68 appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions wereassayed by TLC and terminated as judged by the consumption of starting material.

Visualization of the TLC plates was done with an iodine chamber, UV, p-anisaldehydespray reagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt% in éthanol), ninhydrinreagent, and activated with heat. Work-ups were typically done by doubling the reaction volumewith the reaction solvent or extraction solvent and then washing with the indicated aqueoussolutions using 25% by volume of the extraction volume unless otherwise indicated. Productsolutions were dried over anhydrous Na2SO4 or MgSO4 prior to filtration and évaporation of thesolvents under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo.Flash column chromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was done using Bakergrade flash silica gel (47-61 μιτι) and a silica gel: crude material ratio of about 20:1 to 50:1 unlessotherwise stated. Hydrogénation was done at the pressure indicated in the examples or atatmospheric pressure. 1H-NMR spectra were recorded on a Bruker instrument operating at 300 M Hz, 400 M Hz or 500M Hz and 13C-NMR spectra were recorded operating at 75 M Hz. NMR spectra were obtained asCDCI3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and77.00 ppm) or DMSO-D6 (2.50 ppm and 39.51 ppm) or or CD3OD (3.4 ppm and 4.8 ppm and 49.3ppm), or internai tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were usedas needed. When peak multiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doubletof triplets). Coupling constants, when given, are reported in Hertz ( Hz).

The following abbreviations may be used herein: Et2Û (diethyl ether); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); MeOH (methanol); EtOH (éthanol); EtOAc (ethylacetate); THF (tetrahydrofuran); Ac (acetyl); Me (methyl); Et (ethyl); and Ph (phenyl). EXAMPLES:

Example 1: 7-Pvridin-3-vl-1,5-dihvdro-f 1,21diazepinof4,5,6-cd1indol-6-one 0 A 30 7 ΟγΟ^ΟΗΝ„ ’χχ

NaNO2, Η2Ο 30% HBr (CH3CO2H)

MeO-^O

Br.

POCI3. DMF 1. / och3 ,dmf —->-

2. Ra/Ni, H2, DMF

NH2NH2.H2O, AcOH

MeOH, reflux, 23% CH2CI2) 69% 1(b)

HW-N

Step 1. Préparation of 6-Amino-2-methyl-3-nitro-benzoic acid methyi ester *1(a) 10 5-Methyl-6-nitro-1H-benzo[d][1,3loxazine-2,4-dione (8 g, 36.0 mmol,) prepared from 2-Amino-6-methyl-benzoic acid (Aldrich) as described by Abood, N.A., et al. (1997) Bioorganic & Med. Chem.Lett 7: 2105-2108 and sodium carbonate (3.82, 36.0 mmol) were stirred in methanol (180 mL, 0.1M) at 0 °C for 0.5 hours and then at ambient température for 3 hours. Strongly acidic ion-exchange resin (Dowex® 50 WX4-200) was added until neutral pH and the solution was filtered.The solvent was removed under reduced pressure and silica gel chromatography (60:40hexane/ethyl acetate) afforded Intermediate 1(a) (6.59 g) in 87% yield. 1H-NMR (d6-DMSO): δ 7.88 (d, 1H, J = 9.1 Hz), 6.65 (d, 1H, J= 9.2 Hz), 6.55 (s, 2H), 3.86 (s, 3H),2.38 (s, 3H). LCMS: (M-H+) 209.1

Step 2. Préparation of 6-Bromo-2-methyl-3-nitro-benzoic acid methyi ester 1(b)

Intermediate 1(a) (0.29 g, 1.38 mmol) was added to an ice-cold solution of HBr (30% in acetic15 acid, 1.6 mL) and water (3.0 mL). Sodium nitrite (0.103 g, 1.5 mmol) in water (2.0 mL) was addeddropwise and the mixture stirred at 0 °C for 0.5 hours. Excess nitric acid was destroyed by theaddition of urea. The diazonium sait solution was added to a mixture of CuBr (0.6 g, 4.18 mmol), HBr (30% In acelic acid, 3.5 mL) and water (5.0 mL) at 35 °C and the reaction mixture was heated at 80 °C for 1.5 hours. The resulting precipitate was filtered and washed with water to afford 20 Intermediate 1(b) (0.307 g) in 81% yield. 1H-NMR (ds-DMSO): δ 7.99 (d, 1H, J = 8.8 Hz), 7.85 (d, 1H, J = 8.8 Hz), 3.94 (s, 3H), 2.39 (s, 3H). 70

Step 3. Préparation of 5-Bromo-1W-indole-4-carboxylic acid methyl ester 1(c)

Intermediate 1(b) (2.6 g, 9.5 mmol) was dissolved in anhydrous W,A/-dimethylformamide (0.5 M,20 mL). /\/,A/-Dimethylformamide dimethyl acetal (3.0 eq, 3.8 mL, 28.5 mmol) was added under anargon atmosphère at ambient température with stirring. The mixture was heated at 130 °C for 5 5 hours and cooled to ambient température. W,/V-Dimethylformamide and the unreacted N,N-dimethylformamide dimethyl acetal was removed under reduced pressure (35 °C, c.a. 5 mm Hg). ' Toluene (~50 mL) was added and the volatiles removed under vacuum. The crude enamine wasdissolved in /V,/V-dimethylformamide (0.2 M, 50 mL) followed by the addition of Ra/Ni (-300 mg).The reaction mixture was stirred under hydrogen atmosphère for 7 hours, filtered over celite and 10 concentrated. Silica gel chromatography (80:20 hexane/ethyl acetate) afforded Intermediate 1(c)(1.1g) in 46% yield. 1H-NMR (d6-DMSO): δ 11.54 (s, 1H), 7.51 (d, 1H, J= 1.8 Hz), 7.49 (dd, 1H, J= 8.5, 0.8 Hz), 7.33(dd, 1H, J= 8.7 Hz), 6.50-6.47 (m, 1H), 3.92 (s, 3H). LCMS: (M+H+) 252.1 15

Step 4. Préparation of 5-Bromo-3-formyl-1H-indole-4-carboxylic acid methyl ester 1 (d) A premixed Vilsmeier reagent consisting of POCI3 (0.53 mL, 5.7 mmol) in /V,/V-dimethylformamide(1.2 mL, 15.6 mmol) was added dropwise at 0 °C, to Intermediate 1(c) (0.66 g, 2.6 mmol) inanhydrous CH2CI2 (13 mL, 0.2 M) with vigorous stirring. The mixture was stirred for 0.5 hours at 20 ambient température, quenched with aqueous sodium acetate (2.0 M, 10 ml) and neutralized withsolid Na2CO3. The mixture was partitioned between ethyl acetate (50 mL) and H2O (10 mL). Thelayers were separated and the aqueous layer was extracted with ethyl acetate (1 X 20 mL). Theorganic layers were combined, washed with brine, dried over Na2SO4 and concentrated to giveIntermediate 1(d) (0.51 g) in 69% yield. 25 1H-NMR (d6-DMSO): δ 12.54 (s, 1H), 9.80 (s, 1H), 8.43 (s, 1H), 7.59-7.48 (m, 2H), 3.91 (s, 3H).LCMS: (M+H+) 306.0

Step 5. Préparation of 3-Formyl-5-pyridin-3-yl-1H-indoie-4-carboxylic acid methyl ester 1(e) A solution of Intermediate 1(d) (0.05 g, 0.18 mmol), 3-boronic acid pyridine (0.034 g, 0.27 mmol),palladium (II) acetate (0.004 g, 0.0018 mmol), triphenylphosphine (0.009 g, 0.035 mmol) and 30 triethylamine (0.08 mL, 0.55 mmol) in Λ/,/V-dimethylformamide (0.7 mL, 0.25 M) was heated at100 °C for 96 hours. The reaction mixture was cooled and filtered through ceiite, providing aftercolumn chromatography Intermediate 1(e) (0.015 g) in 30% yield. LCMS: (M+H+) 281.1

Step 6. Préparation of Titie Compound: 7-Pyridin-3-yl-1,5-dihydro-[1,2]diazepino[4,5,6- 35 ccQindol-6-one A solution of Intermediate 1(e) (0.015 g, 0.054 mmol), hydrazine (0.008 mL, 0.135 mmol) andacetic acid (0.020 mL, 2%) in anhydrous methanol (1.0 mL, 0,05 M) was heated at 80 °C for 24 013017 71 hours. The reaction mixture was cooled at ambient température and the title compound (0.0035g) was obtained after a préparative HPLC purification in 23% yield. 1H-NMR (de-DMSO): δ 12.03 (s, 1H), 9.97 (s, 1H), 8.69 (s, 1H), 8.65 (d, 1H, J = 4.6 Hz), 8.09 (d,1H, J = 8.3 Hz), 7.77 (d, 1H, J = 2.7 Hz), 7.76-7.68 (m, 1H), 7.61 (d, 1H, J = 8.4 Hz), 7.54 (s, 1H),7.01 (d, 1H, J =8.4 Hz). LCMS: (M+H+) 263.1

Example 2: 8-Amino-1.5-dihvdro-i1,2ldiazepinof4.5,6-cdlindol-6-one (hvdrochloric sait) W’0"’

1. 7 DCHa, 2. Pd/C, H2, 55 p.s.i.it,21%

DMF

HN-N

HCI.H2N

Step 1. Préparation of 2-Methyl-3,5-dinitro-benzoic acid methyl ester 2(a)

Concentrated sulfuric acid (0.5 mL) was added slowly at ambient température with stirring to 2-methyl-3,5-dinitro-benzoic acid (5.22 g, 23.06 mmol) in anhydrous methanol (200 mL). Afterrefluxing ovemight under an argon atmosphère, the reaction was determined to be about 50%complété. Toluene (100 mL) was used to azeotrope the H2O generated from the reaction, andfresh anhydrous methanol (300 mL) and H2SO4 (0.5 mL) were added and the mixture was againrefluxed overnight under an argon atmosphère at which point the volatile components werereduced in vacuo. Ethyl acetate and 5% aqueous NaOH were added with stirring, and the productwas extracted into the ethyl acetate. The ethyl acetate was then washed twice each with 5%aqueous NaOH and saturated aqueous NaHCO3, once with brine and dried with Na2SO4 to giveIntermediate 2(a) (4.65 g, 19.37 mmol) as a white solid in 84% yield.

Step 2. Préparation of 6-Amino-1H-indole-4-carboxylic acid methyl ester 2(b)

Using a modification of the procedure described by Coe, J.W., et. al. (1996) Tetrahedron Letters37(34):6045-6048, Intermediate 2(a) (268 mg, 1.12 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.56 mL) and N,/V-dimethylformamide dimethyl acetal (0.445 mL, 3.35 mmol)was added under an Ar atmosphère with stirring. The mixture was heated at 120 °C ovemight atwhich point the unreacted W,/V-dimethylformamide dimethyl acetal was removed under vacuum(35-40 °C, c.a. 5 mm Hg). To the resulting red enamine was added anhydrous N,N-dimethylformamide (c.a. 10 mL) and 10% palladium on carbon (230 mg) and the mixture washydrogenated at 55 p.s.i. for 5 hours. The Pd catalyst was filtered through diatomaceous earth 013017 72 and H2O was added to the filtrate. The aqueous component was then extracted multiple timeswith ethyl acetate and the combined extracts were dried with Na2SO4, filtered, and the volatilecomponents were removed in vacuo to give the crude Intermediate 2(90 mg) as a brown glass.Purification was carried out by eluting through a silica plug with 20% ethyl acetate and 20% 5 éthanol in hexane giving Intermediate 2(b) (45 mg, 0.24 mmol) as a brown solid in 21 % yield.

Step 3. Préparation of Titie Compound: 8-Amino-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one (hydrochioric sait)

With ice bath cooling under argon, to Intermediate 2(b) (45 mg, 0.24 mmol) in anhydrous CH2CI2(0.3 mL) and /V,/V-dimethylformamide (0.3 mL) was added dropwise a premixed Vilsmeier reagent 10 (0.1 mL) consisting of POCI3 (0.47 mL) in Λ/,/V-dimethylformamide (0.77 mL). After removing the ice bath, the mixture was stirred for 0.5 hours at which point the reaction was again cooled in anice bath and an additional Vilsmeier reagent (0.1 mL) was added. Following removal of the icebath, the réaction was stirred 0.5 hours and then poured onto ice. Ethyl acetate was addedfollowed by aqueous saturated NaHCO3. The product was then extracted into ethyl acetate, 15 washed with brine, dried with Na2SO4, and filtered to give (by LCMS) di-W-formylated 3-formyl-1H-indole-4-carboxylic acid methyl ester (37 mg, 0.13 mmol) as a brown glass which was thendissolved in anhydrous methanol (2.2 mL). Acetic acid (0.022, 0.384 mmol) and H2NNH2.H2O(0.038 mL, 0.78 mmol) were added, and the mixture was refluxed for 2 hours. After removing thevolatile components in vacuo, the crude product was dissolved in H2O and filtered, the water was 20 lyophilized and the resulting yellow glass (36 mg) was chromatographed on silica gel eluting with10% methanol in CH2CI2. Fractions j'udged pure were pooled, and the product in methanol wasacidffied with 1M HCl. The volatile components were removed in vacuo using acetonitrile toazeotrope remaining water affording the titie compound (4 mg, 0.016 mmol) as a brown solid in7% yield. 25 ’H NMR (d6-DMSO): δ 11.99 (s, 1H), 10.40 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.52-7.41 (m, 2H).HRMS (MALDI M+H+) Calcd for Ci0HeN4O: 201.0771. Found: 201.0776. 013017 73

Altenative Method for the Préparation of Intermediate 2(b) hvdrochloride:

Pd/C, H2, EtOAc -». 4N HCl (Dioxane)MeOH, 92%

Step 4. Préparation of 2-(2,2-Dimethoxy-ethyl)-3,5-dinitro-benzoic acid methyl ester 2(c)IAttn; 2-(2-Dimethylamino-vinyl)-3,5-dinitro-benzoic acid methyl ester generated during (first stepof Step 4) enamine formation could lead to explosive décomposition!] 2-Methyl-3,5-dinitro-benzoic acid (100 g, 0.442 mol) was dissofved in anhydrous N,N-dimethylformamide (1 M, 400 mL). /V,W-Dimethylformamide dimethyl acetal (188 mL, 1.33 mol)was added under an argon atmosphère over 10 min at ambient température with stirring. Themixture was heated at 110 °C for 5 hours behind a shieid, and cooled at ambient température.Λ/,/V-Dimethylformamide and the unreacted /V,/V-dimethylformamide dimethyl acetal were removedunder reduced pressure (35 °C, c.a. 5 mm Hg). Toluene (~50 mL) was added and the volatilesremoved under vacuum. 2-(2-Dimethylamino-vinyl)-3,5-dinitro-benzoic acid methyl ester, isolatedas a dark red soiid, was mixed with anhydrous methanol (880 mL) and chlorotrimethylsilane (140mL, 1.10 mol) was added over 10 min. The solution was heated at reflux (oil bath 67-70 °C) underargon for 20 hours, cooled to ambient température, and the volume of the mixture was reducedunder vaccuum to approximately 100 mL. The precipitated soiid was collected by filtration andwashed with cold methanol (100 mL). The dark brown soiid was dried under vacuum, trituratedwith acetone (100 mL), again collected by filtration and washed with diethyl ether (150 mL) toafford intermediate 2(c) (79 g). The mother liquor from the first précipitation and the varioustriturations were combined and concentrated. Additional intermediate 2(c) (21 g) was thenrecrystallized from cyclohexane/ethyl acetate (9:1) providing a second batch. Again the resultingmother liquor was reduced in vacuo and a third batch of Intermediate 2(c) (4 g) was recrystallizedfrom acetone/H2O (6:4). The combined yield for ali three batches of Intermediate 2(c) (104 g) was75%.

Step 5. Préparation of 6-Amino-1W-indoie-4-carboxylic acid methyl ester hydrochioride 2(b) Q130 1 7 74 10

Intermediate 2(c) (20 g, 63.6 mmol) was dissolved in anhydrous ethyl acetate (350 mL) and 10%palladium on carbon (7.4 g, 6.36 mmol) was added under argon. The mixture was hydrogenatedat 1 atm until the reaction was judged complété by LCMS. The Pd catalyst was removed byfiltering through diatomaceous earth, and the filtrate was reduced in vacuo. The crude 3,5-diamino-2-(2,2-dimethoxy-ethyl)-benzoic acid methyl ester was dissolved in anhydrous methanol(40 ml), and 4.0 M HCl in dioxane (160 mL) was added. The mixture was stirred at ambienttempérature for one hour. The precipitated solid was collected by filtration and washed withCH2CI2 and diethyl ether and dried under vacuum to produce Intermediate 2(b) (hydrochloride)(11.85 g) as a gray solid. The filtrate was concentrated and more Intermediate 2(b) hydrochloride(1.48 g) was precipitated. The combined yield for both batches of Intermediate 2(b) (13.33 g) was92%

Example 3: A/-(6-Oxo-5.6-dihvdro-1 W1,21diazepinof4,5,6-ccfiindol-8-vl)-acetamide

Vf

1. ! DCH3.DMF

3(b)

NH2NH2.H2O, AcOH

MeOH, reflux, 51% 15

Pd/C, H2, 55 p.s.i.61%

POCI3. DMF CH2CI2, 44% HN—NOasZ \\

AcHN

Step 1. Préparation of 5-Acetylamino-2-methyl-3-nitro-benzoic acid methyl ester 3(a)

To 5-amino-2-methyl-3-nitro-benzoic acid methyl ester (428 mg, 2.04 mmol), prepared asdescribed by Cannon et. al. (1984) J. Med. Chem. 27:386-389, in CH2CI2 (4 mL) was addedtriethylamine (1.71 mL, 12.2 mmol), acetic anhydride (0.77 mL, 8.14 mmol) and 4-(dimethylamino)pyridine (30mg, 0.25 mmol) with stirring at ambient température. After stirringovernight, LCMS indicated a mixture of mono and diacetylated products. Saturated aqueousNaHCO3 was added, and the mixture was again allowed to stir overnight. Additional CH2CI2 wasadded, and the layers were separated. The organic layer was reduced and ethyl acetate wasadded. The organic layer was washed with saturated aqueous NaHCO3, with H2O, with saturatedaqueous KHSO4, with brine, dried (Na2SO4), filtered and evaporated to an oil which was then re-dissolved in a minimal amount of ethyl acetate. Hexane was added and the resulting precipitate 20 013017 75 was isolated as tan solids (469 mg) which were then purified on silica gel, eluting with 1:2 ethylacetate:hexane followed by 1:1 ethyl acetate:hexane, to afford Intermediate 3(a) (133 mg, 0.53mmol) as a cream solid in 26% yield. (5-diacetylamino-2-methyl-3-nitro-benzoic acid methyl ester(248 mg, 0.84 mmol) was also isolated.) 1H NMR (d6-DMSO): δ 10.46 (br s, 1H, exchanges), 8.34 (s, 1H), 8.14 (s, 1H), 3.89 (s, 3H), 2.43(s,3H), 2.08 (s, 3H). LCMS: (M-H)'251.3.

Step 2. Préparation of 6-Acetylamino-1-hydroxy-1W-indole-4-carboxylic acid methyl ester3(b)

To Intermediate 3(a) (117 mg, 0.46 mmol) in anhydrous /V,/V-dimethylformamide (0.5 mL) wasadded, under an Ar atmosphère with stirring, W,/V-dlmethylformamide dimethyl acetal (0.185 mL,1.39 mmol). The mixture was heated at 120 °C for 5-6 hours at which point the unreacted N,N-dimethylformamide dimethyl acetal was removed under vacuum (35-40 °C, c.a. 5 mm Hg). To theresulting red enamine was added anhydrous Λ/,/V-dimethylformamide (c.a. 20 mL), ethyl acetate(10 mL) and 10% palladium on carbon (150 mg). The mixture was hydrogenated at 55 p.s.i. for 4hours at which point the /V,A/-dimethylformamide was removed in vacuo, methanol was added,and the Pd catalyst was removed by filtration. Again the volatile components were removed invacuo. Following diethyl ether trituration, the triturate was evaporated to afford crude Intermediate3(b) (70 mg, 0.28 mmol) as tan solids in 61% yield which were carried forward without furtherpurification. LCMS: (M-H)'247.3.

Step 3. Préparation of 6-Acetylamino-1H-indole-4-carboxylic acid methyl ester 3(c)

To Intermediate 3(b) (39 mg, 0.16 mmol) in acetic acid (1 mL) was added zinc dust (206 mg, 3.15mmol) with stirring. The mixture was heated at 50 °C for 0.5 hours and then 65 °C for 0.5 hoursduring which time the mixture turns green. After cooling to room température methanol is addedand the mixture is filtered though diatomaceous earth rinsing several fîmes with methanol.Following évaporation the resulting tan solids are triturated with methanol and the volatilecomponents of the triturate are remove in vacuo to afford crude Intermediate 3(c) (35 mg, 0.15mmol) as tan solids in 94% crude yield which were then carried on without further purification.LCMS: (M-H)'231.2.

Step 4. Préparation of 6-Acetylamino-3-formyl-1M-indole-4-carboxylic acid methyl ester 3(d)

With ice bath cooling under argon, 0.2 mL of a premixed Vilsmeier reagent consisting of POCI3(0.47 mL) in Λ/,/V-dimethylformamide (0.77 mL) was added in two equal portions to Intermediate3(c) (35 mg, 0.15 mmol) in 1:1 CH2CI2: Λ/,/V-dimethylformamide (1 mL). After 0.5 hours thereaction was quenched with water and extracted with ethyl acetate. The aqueous layer was thenbasified to about pH 8 with 5% aqueous NaOH and extracted again with ethyl acetate. Thecombined ethyl acetate extracts were dried with Na2SO4, filtered and evaporated to give 013017 76

Intermediate 3(d) (19 mg, 0.07 mmol) as yellow solids in 44% crude yield which were thencarried on without further purification. LCMS: (M-H)'259.3.

Step 5. Préparation of Title Compound: N-(6-Oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yI)-acetamide

To Intermediate 3(d) (19 mg, 0.07 mmol) in anhydrous methanol (2.0 mL) was added acetic acid(0.006 mL, 0.1 mmol) and Η2ΝΝΗ2Ή2Ο (11 mg, 0.22 mmoi) and the mixture was refluxed forabout 1 hour after which the volatile components were removed in vacuo and the resulting yellowglass was redissolved in methanol. FoHowing recrystallization from methanol/diethyl ether, the titlecompound (9 mg, 0.04 mmol) was obtained as a yellow powder in 51% yield. 1H NMR (d6-DMSO): δ 11.60 (br s, 1H, exchanges), 10.10 (ε, 1H, exchanges), 9.90 (s, 1H,exchanges), 8.00 (s, 1H), 7.45 (br s, 2H), 7.30 (s, 1H), 1.90 (s, 3H). LCMS: (M+H+) 243.1, (M+Na+) 265.1.

Example 4: 2,2,2-Trifluoro-/\/-(6-oxo-5.6-dihvdro-1 B-H.2ldiazepinof4.5,6-ccflindol-8-vh-acetamide

With stirring, trifluoroacetic anhydride (0.032 mL, 0.23 mmol) was added dropwise to triethylamine(0.088 mL, 0.63 mmol) and the title compound of Example 2 (freebase) (43 mg, 0.21 mmol) inW,W-dimethylformamide (2 mL). After 2.5 hours, additional trifluoroacetic anhydride (0.032 mL,0.23 mmol) was added to drive the reaction to completion at which point diethyl ether was addedto precipitate brown solids (25 mg), which were discarded. The triturate was reduced in volumeand subjected to préparative HPLC (MetaChem Metasil AQ C18 reverse-phase 10pm, 120A,250x21.2 mm column eluting with CH3CN/0.1%TFA in H2O at a flowrate of 20 mL/min using agradient of 5-95% CH3CN over 20 min) affording, after isolation, the title compound (3.7 mg, 0.01mmol) as a brown solid in 6% yield. 1H NMR (d6-DMSO): δ 12.01 (s, 1H), 11.41 (s, 1H), 10.40 (s, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.78(s, 1H), 7.61 (S, ÏH) LCMS: (M-H)'295.2.

Fxample 5: 7-Amino-2-phenvl-1.5-dihvdro-f1.21diazepino[4,5.6-ccflindol-6-one 013017

MeO.

1. POCI3. DMF, CH2CI2 --->» 2. NH2NH2.H2O, AcOHMeOH, reflux, 21 %

Step 1. Préparation of 3-Amino-2-bromo-benzoic acid methyl ester 5(a) 2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 mmol) (prepared from 2-amino-3-nitro- 5 benzoic acid as described by Webber E. S. et al., see patent application number WO 01/16136A2) and SnCI2 (42 g, 223 mmol) were refluxed in methanol (225 mk, 0.2 M) and H2O (5.3 g, 243mmol) for 2 hours. After cooling at ambient température, diatomaceous earth (20 g) anddichloromethane (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) withvigorous stirring. The mixture was filtered and the organic phase was washed with saturated 10 aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and ailvolatiles were removed under reduced pressure to afford Intermediate 5(a) (11.4 g) in 98% yield.1H-NMR (de-DMSO): δ 7.12 (dd, 1 H, J = 8.1, 7.5 Hz), 6.93 (dd, 1 H, J = 8.1, 1.6 Hz), 6.80 (dd, 1H,J = 7.4, 1.6 Hz), 5.57 (s, 2H), 3.81 (s, 3H).

Step 2. Préparation of 3-Acetylamino-2-bromo-benzoic acid methyl ester 5(b) Ο13θΠ 78

Intermediate 5(a) (2.21 g, 9.6 mmol) and acetic anhydride (1.82 mL, 19.2 mmol) were stirred inCH2CI2 (100 mL, 0.1 M) at 22 °C for 24 hours. Volatiles were removed in vacuo and silica gelchromatography afforded Intermediate 5(b) (2.08 g) in 79% yield. 1H-NMR (d6-DMSO): δ 9.58 (s, 1 H), 7.70 (dd, 1 H, J = 6.9, 2.7 Hz), 7.50-7.41 (m, 2H), 3.86 (s, 3H),2.09 (s, 3H). LCMS: (M+H+) 272.0, 274.0

Step 3. Préparation of 3-Acetylamino-2-bromo-6-nitro-benzoic acid methyl ester 5(c)

Intermediate 5(b) (1.0 g, 3.7 mmol) was nitrated in a manner analogous to step 1 of Example 2.intermediate 5(c) (1.0 g, 89%) was obtained after silica gel chromatography. 1H-NMR (de-DMSO): δ 9.83 (s, 1H), 8.3 (d, 1H, J = 9.0 Hz), 8.15 (d, 1H, J = 9.0 Hz), 3.93 (s, 3H),2.20 (s, 3H). LCMS: (M+H+) 315.0, 317.0

Step 4. Préparation of 3-Acetylamino-6-nitro-2-phenylethynyl-benzoic acid methyl ester5(d)

Intermediate 5(c) (0.85 g, 2.7 mmol) was acetylated in a manner analogous to step 3 of Example6 to afford Intermediate 5(d) (0.4 g, 44%) after silica gel chromatography. 1H-NMR (de-DMSO): δ 9.93 (s, 1H), 8.32-8.25 (m, 2H), 7.65-7.59 (m, 2H), 7.53-7.47 (m, 3H), 3.97(s, 3H), 2.25 (s, 3H). LCMS: (M-H+) 337.1

Step 5. Préparation of 5-Nitro-2-phenyl-1H-indole-4-carboxylic acid methyl ester 5(e)

Intermediate 5(d) (0.096 g, 0.28 mmol), copper iodide (0.076 g, 0.4 mmol), Ν,Ν,Ν,Ν-tetramethylguanidine (0.36 mL, 2.8 mmol) were stirred in a mixture of dimethylformamide/dioxane(1:4, 2 mL, 0.15 M) at 90 °C for 2 hours. The reaction mixture was cooled to ambient températureand poured into ethyl acetate (30 mL). The organic layer was washed subsequently with asaturated ammonium chloride solution (3X5 mL), H2O (2X5 mL), saturated aqueous sodiumchloride solution (2X5 mL), dried over sodium sulfate, filtered and volatiles removed in vacuo.Silica gel chromatography afforded Intermediate 5(e) (0.073 g) in 86% yield. 1H-NMR (d6-DMSO): δ 12.50 (s, 1H), 7.98-7.88 (m, 3H), 7.69-7.40 (m, 4H), 7.13 (broad s, 1H),3.97 (s, 3H). LCMS: (M-H+) 295.1

Step 6. Préparation of 5-Amino-2-phenyl-1H-indole-4-carboxylic acid methyl ester 5(f)

In an analogous manner to that of the préparation of Example 2 (step 5), Intermediate 5(e) (0.072g, 0.24 mmol) was hydrogenated to afford Intermediate 5(f) (0.06 g, 95%). 1H-NMR (d6-DMSO): δ 11.68 (s, 1H), 7.86 (d, 2H, J = 7.4 Hz), 7.52-7.43 (m, 3H), 7.31 (dd, 1H, J =7.4, 7.2 Hz), 7.20 (s, 1H), 6.83 (d, 1H, J = 8.5 Hz), 3.94 (s, 3H). LCMS: (M+H+) 235.1 013017 79

Step 7. Préparation of Title Compound: 7-Amino-2-phenyl-1,5-dihydro- [1,2]diazepino[4,5,6-ct/Jindol-6-one

Carried out analogously to steps 4 and 5 of Example 3, Intermediate 5(f) (0.055g, 0.21 mmol) wasformylated and cyclized to provide the title compound (0.012g, 21 %). 5 1H-NMR (d6-DMSO): δ 12.17 (s, 1H), 8.32 (s, 1H), 7.95-7.84 (m, 3H), 7.74 (d, 1H, J = 1.8 Hz),7.55-7.47 (m, 2H), 7.42 (d, 1H, J = 8.6 Hz), 7.37 (dd, 1H, J = 7.4, 7.3 Hz), 5.91 (s, 2H). LCMS: (M+H+) 277.1

Example 6: /V-(6-Oxo-2-phenvl-5.6-dihvdro-1H-[1,2)diazëpino(4.5.6-cd|indol-8-vl-acetamide

MeO. o2n'

P

Br

1. Fe, CH3CO2H, 40 °C 2. (CH3CO2)2O, CH2CI2DMF, rt 3. Fe, (CH3CO2)2OCH3CO2H, 40 °C, 49%

HN~N 10

2. NH2NH2.H2O, AcOHMeOH, reflux, 4% 1. POCI3. DMF, CH2CI2

15 20

Step 1. Préparation of 2-Bromo-3,5-dinitro-benzoic acid methyi ester S(a)

Concentrated sulfuric acid (20 mL) was slowly added to 2-bromo-5-nitro-benzoic acid methyi ester(20.52 g, 78.91 mmol) with stirring. After a few minutes, fuming nitric acid (20 mL) was added andthe mixture was capped and heated at 40°C for approximately 60 hours at which point the flaskwas cooled to ambient température, carefully opened, and the reaction was poured onto ice waterand ethyl acetate. The product was extracted into ethyl acetate and washed twice with H2O, twicewith saturated aqueous NaHCO3, brine, dried (Na2SO4), and filtered to afford Intermediate 6(a)(16.6-1 g, 51.26 mmol) as a r.rsam Rnlirl in 65% yield ’H NMR (d6-DMSO): δ 9.07 (s, 1H), 8.73 (s, 1H), 3.98 (s, 3H). LCMS: (M-CO2CH3)· 245.1, 247.1. 013017 80

Step 2. Préparation of 3,5-Bis-acetylamino-2-bromo-benzoic acid methyl ester 6(b)

To acetic acid (250 mL) at room température was added Intermediate 6(a) (15.49 g, 50.79 mmol).The mixture was placed in an oil bath at 40 °C for c.a. 10 min and stirred vigorously under an Aratmosphère until the soution went clear. Iran powder (25.34 g, 453.72 mmol) was added and themixture was heated at 40 °C for c.a. 6 hours. The mixture was fiitered through diatomaceousearth, rinsing with methanol. The combined filtrate and rinses were evaporated to give orangesolids, which were determined to be a mixture of products (13.2 g) resulting from incomplèteréduction of the nitro groups. This mixture (13.1 g) in CH2CI2 (48 mL) and Λ/,/V-dimethylformamide(5 mL) was then treated with acetic anhydride (36 mL, 382 mmol) and stirred overnight under anAr atmosphère. The CH2CI2 was evaporated and the mixture was partitioned between ethylacetate and saturated aqueous NaHCO3 .The aqueous layer was extracted twice with ethylacetate and the combined extracts were washed successively with 1:1 H2O:saturated aqueousNaHCO3 (multiple washings), 0.5 M aqueous HCl (X2), saturated aqueous NaHCO3 (X2) andbrine. The ethyl acetate solution was then dried (Na2SO4), fiitered and evaporated to give yellowsolids, which were then triturated with diethyl ether (c.a. 75 mL) to give a mixture of acetylatedproducts (11.4 g) as a yellow solids. A portion of this mixture of acetylated products (5.5 g) inacetic acid (17.4 mL) was then treated with acetic anhydride (16.5 mL, 174 mmol) and ironpowder (9.74 g, 174 mmol) and heated at 40°C under an Ar atmosphère overnight. Methanol wasthen added and the reaction was stirred at room température for c.a. 1.5 hours. Then 9:1CH2CI2: methanol was added, and the mixture was fiitered through diatomaceous earth, rinsingwith 9:1 CH2CI2:methanol. The combined filtrate and rinses were evaporated and again methanoiwas added and the mixture was stirred c.a. 0.5 hours after which the methanol was evaporated.Ethyl acetate was added followed by hexane to precipitate orange solids (6.9 g) which werecollected. Silica gel chromatography eluting with 1:1 acetone:hexane which afforded, afterisolation, Intermediate 6(b) (4.1 g, 12.46 mmol) as a cream solid in 49% yield.

Step 3. Préparation of 3,5~Bis-acetylamino*2-phenylethynyl-benzoic acid methyl ester 6(c)

With stirring, argon was bubbled into anhydrous toluene (18 mL) containing Intermediate 6(b)(1.08 g, 3.29 mmol). Tributyl-phenyiethynyl-stannane (1.73 mL, 4.94 mmol) andtetrakis(triphenylphosphine) palladium(O) (310 mg, 0.28 mmol) were added sequentially and moreAr was bubbled into the reaction. After capping tightly, the mixture was heated at 90 °C overnightunder an argon atmosphère. After cooling to ambient température, H2O, and saturated aqueousKHSO4 were added and the product was extracted into ethyl acetate and isolated. Following silicaoel chromatography eluting with 2:3 acetone:hexane, fractions judged pure were pooled.Intermediate 6(c) (1.14 g, 3.25 mmol) was isolated, found to be contaminated by approximately 5-10% triphenylphosphine oxide, and carried on to the next step without further purification. 013017 81 1H NMR (de-DMSO): δ 10.30 (s, 1H), 9.50 (s, 1H), 8.23 (s, 1H), 8.08 s, 1 H), 7.63-7.51 (m, 2H,contaminated by Ph3PO), 7.50-7.38 (m, 3H, contaminated by Ph3PO), 3.90 (s, 3H), 2.17 (s, 3H),2.05 (s, 3H). LCMS: (M+H+) 351.1, (M+Na+) 373.1, (M-H‘) 349.1. 5 Step 4. Préparation of 6-Acetylamino-2-phenyl-1 W-indole-4-carboxylic acid methyi ester6(d)

To the impure intermediate 6(c) (853 mg, 2.4 mmol) is added concentrated sulfuric acid (15 mL).After stirring 0.5 hours, the mixture is carefully poured onto methanol (30 mL) with vigorousswirling. Ethyl acetate (c.a. 300 mL) and H2O (c.a.100 mL) are added. The aqueous layer is 10 extracted three times with ethyl acetate, and the combined extracts are washed with saturatedaqueous NaHCO3 until the évolution of CO2 ceases. The product in ethyl acetate is then washedwith brine, dried (Na2SO4), filtered and volatile components evaporated to afford crudeIntermediate 6(d) (790 mg, c.a. 2.4 mmol) as a yellow powder which was carried on withoutfurther purification. 15 1H NMR (d6-DMSO): δ 11.75 (s, 1H, exchanges), 10.07 (s, 1H, exchanges), 8.33 (s, 1H), 7.90-7.80 (m, 3H), 7.66-7.23 (m, 4H, partially obscured), 3.93 (s, 3H), 2.07 (s, 3H). LCMS: (M+H+) 309.1, (M+Na+) 331.1, (M-H)' 307.1.

Step 5. Préparation of Title Compound: N-(6-Oxo-2-phenyl-5,6-dihydro-1H- [1,2]diazepino[4,5,6-ccf|indoi-8-yl-acetamide 20 Crude Intermediate 6(d) (312 mg, c.a. 1 mmol) in Λ/,/V-dimethylformamide (2 mL) and CH2CI2 (5mL) was treated with Vilsmeier reagent (0.9 mL) in a manner similar to that described for Example3, step 4. After removal of the CH2CI2, adjusting the pH to c.a. 8 with 1N NaOH and removal of thevolatile components in vacuo, the yellow solids were triturated with ethyl acetate and methanol.The triturate was evaporated to afford the crude 6-acetylamino-3-formyl-2-phenyl-1tf-indole-4- 25 carboxylic acid methyi ester (405 mg) as a yellow solid contaminated with salts from the aqueousquench. In a procedure similar to that described for Example 3, step 5, anhydrous methanol (15mL), acetic acid (0.084 mL, 1.47 mmol) and H2NNH2'H2O (0.147 mL, 3.03 mmol) were then addedand the mixture was refluxed for 2 hours. The volatile components were evaporated and theresulting solids were triturated with methanol to dissolve the product while leaving behind most of 30 the insoluble solids. The triturate was evaporated, and this process was repeated. The secondtriturate was evaporated to give yellow solids (70 mg) enriched in product which were thensubjected to silica gel chromatography eluting with hexane:ethyl acetate:ethanol (4:1:1) to give thelllle uuuipound (12 mg, 0.04 mmol) after isolation aa a yellow powder in approximately 4% overallyield. 35 1H NMR (ds-DMSO): δ 12.10 (s, 1H, exchanges), 10.33(s, 1H, exchanges), 10.06(s, 1H, exchanges), 8.17 (s, 1H), 7.70-7.43 (m, 7H), 2.05 (s, 3H). 82 LCMS: (M+H+) 319.1, (M+Na+) 341.1, (M-Hf 317.

Altenative Method for the Préparation of Intermediate 6(b). MeO^>0 MeO^.0 A” Fe, (CH3CO2)2O- il O2N'X^^XNO2 CH3CO2H, 40 °C, 56% AcHN^^^NHAc (b) 10 15

To acetic acid (10 mL) at room température was added acetic anhydride (10.0 ml_, 106 mmol),iron powder (5.5 g, 98 mmol) and Intermediate 6(a) (3.0 g, 9.8 mmol). The mixture was placed inan oil bath at 43 °C and stirred vigorously under argon for 48 hours. The thick slurry goes fromorange to tan in color. Additîonal acetic acid (2 mL), acetic anhydride (2 mL, 21.2 mmol), and ironpowder (1.0 g, 17.9 mmol) were added, and the mixture was stirred at 43 °C for an additîonal 24hours whereupon the mixture was poured into 10% methanol in CH2CI2 (300 mL) and filteredthough diatomaceous earth. The filtrate was concentrated and ethyl acetate (300 mL) and H2O(300 mL) were added. The product was extracted into ethyl acetate and washed twice with H2O,twice with brine, dried (MgSO4), and filtered. Following recrystallization from hot ethyl acetate (10mL), collection by filtration and subséquent washing of the solids with CH2CI2 (5 mL) and diethylether (30 mL), Intermediate 6(b) (1.8 g, 5.47 mmol) was obtained as a white solid in 56% yield.Example 7: 8-Amino-2-phenvl-1,5-dihvdro-f1.21diazepinof4,5.6-cdlindol-6-one

1. POCI3. DMF, CH2CI2

4N HCl (Dioxane), MeOH, 90 °C

2. NH2NH2.H2O, AcOHMeOH, reflux, 30%

HN-N

H,N

Step 1. Préparation of 6-Amino-2-phenyl-1H-indole-4-carboxylic acid methyl ester(hydrochlorïc sait) sait 7(a) 20 Intermediate 6(d) of Example 6 (9.3 g, 30.2 mmol) and anhydrous 4M HCl in dioxane (160 mL,604 mmol) were heated in anhydrous methanol (160 mL) at reflux for 3 hours, cooled to ambienttempérature and volatiles removed in vacuo. The resulting solid was triturated with ethylacetate/CH2CI2 (1:1, 50 mL) and dried to afford Intermediate 7(a) (8.7 g) in 95% yield. 013017 83 1H-NMR (ds-DMSO): δ 12.26 (s, 1 H), 10.10 (broad, 1H), 7.93 (d, 2H, J = 7.7 Hz), 7.71 (d, 2H, J =12.2 Hz), 7.52 (dd, 2H, J= 7.7, 7.6 Hz), 7.43-7.36 (m, 2H), 3.96 (s, 3H). LCMS: (M+H+) 267.2.

Step 2. Préparation of Title Compound: 8-Amino-2-phenyl-1,5-dihydro-[1,2]diazepino[4,5,6-5 cdJindol-6-one

In two steps, analogous to steps 4 and 5 of Example 3, Intermediate 7(a) (8.7 g, 28.7 mmol) wascyclized to afford the title compound (5.47 g, 69%). 1H-NMR (d6-DMSO): δ 11.53 (s, 1H), 10.15 (s, 1H), 7.62-7.40 (m, 6H), 6.98 (d, 1H, J = 1.8 Hz),6.65 (d, 1 H, J = 1.8 Hz), 5.21 (s, 2H). 10 LCMS: (M+H+) 277.2.

Example 8: /V-(6-Oxo-2-phenvl-5,6-dihvdro-1/-/-f1,2ldiazepinof4,5.6-ccflindol-8-yl)-succinamic acid

Succinic anhydride (3 eq, 0.022 g) was added to a solution of the title compound of Example 7(0.02 g, 0.072 mmol) in Λ/,/V-dimethylformamide (0.7 M, 1 mL) and methanol (2.5 M, 0.3 mL). The 15 reaction mixture was stirred at 22 °C for 24 hours and concentrated under reduced pressure. Theyellow soiid was triturated with methanol (1.0 mL) and collected by filtration. Following washeswith methanol (4 mL) and diethyl ether (5.0 mL), the title compound (21 mg) was obtained in 77%yield. 1H-NMR (d6-DMSO): δ 12.03 (S, 1H), 10.31 (s, 1H), 10.09 (s, 1H), 8.12 (s, 1H), 7.68-7.45 (m, 7H), 20 2.60-2.53 (m, 4H). LCMS: (M+H+) 377.1.

Example_9;_JV-(6-Oxo-2-phenvl-5.6-dihvdro-1H-f1.21diazepinof4.5.6-cdlindol-8-vl)- methanesulfonamide

25 Methanesuifonyl Chloride (1.5 eq, 0.003 g) was added to a solution of the title compound ofExample 7 (0.005 g, 0.018 mmol) in CH2CI2 (0.045 M, 0.4 mL) and pyridine (0.045 M, 0.4 mL).The mixture was stirred at 22 °C for 24 hours and concentrated under reduced pressure. Silica gelchromatography (triethylamine/methanol/ CH2CI2; 1:5:94) afforded the title compound (1.7 mg) in30% yield. 30 1H-NMR (ds-DMSO): δ 12.15 (s, 1H), 10-40 (s, 1H), 9.71 (s, 1H), 7.70-7.43 (m, 8H), 2.30 (m, 3H). 013017 LCMS: (M+H+) 355.1.

Example 10: 1-(6-Oxo-2-phenvl-5.6-dihvdro-1H-n.2ldiazepinol4.5,6-ccnindol-8-vl)-pvrrolidine-2.5- dione 84

Triethylamine (0.18 mmol, 0.025 mL) and O-(7-azabenzotriazol-1-yl)-/V,/V,/y’,/tf-tetramethyluronium hexafluorophosphate (0.04 mmol, 0.013 g) were added to a solution of thetitle compound of Example 8 (0.013 g, 0.036 mmol) in /V,W-dimethylformamide (0.05 M, 0.75 mL).The reaction mixture was stirred at 22 °C for 12 hours and concentrated under reduced pressure. 10 The yellow solid was triturated with methanol (3.0 mL), collected by filtration, and washed withmethanol (4.0 mL) and diethyl ether (5.0 mL) to afford the title compound (5.8 mg) in 47% yield.1H-NMR (d6-DMSO): δ 12.38 (s, 1H), 10.44 (s, 1H), 9.71 (s, 1H), 7.74-7.42 (m, 8H), 2.79 (m, 3H).LCMS: (M+H+) 359.1.

Example 11: 2-Methvl-cvclopropanecarboxvlic acid(6-oxo-2-phenvl-5.6-dihvdro-1Z7- 15 ί 1.21diazepinoi4.5.6-cdlindol-8-vl)-am ide

2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in /V,W-dimethylformamide(1.0 mL). 0-(7-azabenzotriazol-1-yl)-A/,W,A/’,/\/-tetramethyluronium hexafluorophosphate (25 mg, 20 0.065 mmol) was added and the reaction was stirred ovemight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, elutingwith 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, theresulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) asyellow powder in 36% yield. 25 1H-NMR (d6-DMSO): δ 12.03 (s, 1H), 10.32 (s, 1H), 10.27 (s, 1H), 8.13 (s, 1H), 7.67-7.48 (m, 7H),1.54 (m, 1H), 1.11 (s, 1H), 1.09 (d, 3H), 1.07 (m, 1H), 1.03 (m, 1H). LGMS: 309.1, (M-rNa+) 381.1. 013017 85

Example 12: /V-(6-Oxo-2-phenvl-5,6-dihvdro-1H-f1.2)diazepinor4,5,6-cdlindol-8-vl)-2-tetrazol-1-vl- acetamide

Préparation of example 12 from the title compound of Example 7 (15 mg, 0.054 mmol), tetrazol-1-yl-acetic acid (8 mg, 0.062 mmol), triethÿlamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-/tf,A/,A/’,/V-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) inW,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional tetrazol-1-yl-acetic acid acid (1.0 mg, 0.008 mmol) and O-(7-azabenzotriazol-1-yl)-/V,/\/,/V'/\/'-tetramethyluronium hexafluorophosphate (3.0 mg, 0.008 mmol) were added after c.a. 18 hours todrive the reaction to completion. Filtration, concentration and recrystallization afforded the titlecompound (12 mg, 0.031 mmol) as a yellow powder in 58% yield. 1H-NMR (d6-DMSO): δ 12.13 (s, 1H), 10.71 (s, 1H), 10.39 (s, 1H), 9.44 (s, 1H), 8.07 (m, 1H),7.68-7.47 (m, 7H), 5.05 (s, 2H). LCMS: (M+H+) 387.2, (M+Na+) 409.1.

Example 13: 2-Cyclopentyl-/V-(6-oxo-2-phenvl-5,6-dihvdro-1/-/-f1,21diazepinof4.5,6-cdlindol-8-vl)- acetamide

Préparation of example 13 from the title compound of Example 7 (15 mg, 0.054 mmol),cyclopentyl-acetic acid (8 mg, 0.062 mmol), triethÿlamine (0.030 mL, 0.22 .mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,A/’,/V-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) indimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (1:1 ethyl acetate:hexane), also in an analogous manner, foliowed by diethylether trituration afforded the title compound (3 mg, 0.008 mmol) as a yellow powder in 14% yield.1H-NMR (d6-DMSO): δ 12.03 (s, 1H), 10.32 (s, 1H), 9.99 (s, 1H), 8.17 (s, 1H), 7.67-7.49 (m, 7H),2.33-2.26 (m, 3H), 1.78 (m, 2H), 1.65-1.53 (m, 4H), 1.22 (m, 2H). LCMS: (M+H+) 387.2, (M+Na+) 409.2. 013017

Example 14: 2-Methvl-A/-f6-oxo-2-phenyl-5,6-dihvdro-1H-f1.21diazepino[4.5.6-ccflindol-8-vl)- nicotinamide 86

HN—N

Préparation of example 14 from the title compound of Example 7 (15 mg, 0.054 mmol), 2-methyl-nicotinic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-W,M/V;/V-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in/V,W-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (ethyl acetate), also in an analogous manner, followed by diethyl ether triturationafforded the title compound (7 mg, 0.018 mmol) as a yellow powder in 33% yield. 1H-NMR (de-DMSO): δ 12.13 (s, 1H), 10.57 (s, 1H), 10.36 (s, 1H), 8.57 (m, 1H), 8.25 (s, 1H), 7.90(m, 1H), 7.84 (m, 1H), 7.68 (m, 2H), 7.61-7.50 (m, 4H), 7.34 (m, 1H), 2.60 (s, 3H). LCMS: (M+H+) 396.2, (M+Na+) 418.1.

Example 15: 4.4,4-Trifluoro-/V-(6-oxo-2-phenvl-5.6-dihvdro-1H-[1.2ldiazepinof4,5.6-cd1indol-8-yl)- butyramide

HN—N

Préparation of example 15 from the title compound of Example 7 (15 mg, 0.054 mmol), 4,4,4-trifluorobutyric acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,W’,/V’-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in/V,/V-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (1:1 ethyl acetate.hexane), also in an analogous manner, followed by diethylether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.1H-NMR (d6-DMSO): δ 12.09 (s, 1H), 10.34 (s, 1H), 10.22 (s, 1H), 8.14 (s, 1H), 7.68-7.50 (m, 7H),2.62 (m, 4H). LCMS: (M+H+) 401.1, (M+Na+) 423.0.

Example 16: 4-Methvl-i1.2.31thiadiazole-5-carboxvlic acid(6-oxo-2-phenvl-5.6-dihvdro-1H- ft,21diazepinor4.5.6-cdlindol-8-vl)-amide O: 013017 87

Préparation of example 16 from the title compound of Example 7 (15 mg, 0.054 mmol), 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V’,N'-tetramethyluronium hexafluorophosphate (25mg, 0.065 mmol) in /V,A/-dimethylformamide (1.0 mL) was carried out analogously to Example 11.Additional 4-methyl-I1,2,3]thiadiazole-5-carboxylic acid (1.0 mg, 0.006 mmol) and O-(7-azabenzotriazol-1-yl)-W,A/,W’,/V-tetrarnethyluronium hexafluorophosphate (2.0 mg, 0.006 mmol)were added after c.a. 18 hours to drive the reaction to completion. Silica gel chromatography, alsoin an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg,0.017 mmol) as a yellow powder in 32% yield. 1H-NMR (d6-DMSO): δ 12.21 (s, 1H), 10.85 (s, 1H), 10.41 (s, 1 H), 8.18 (s, 1H), 7.81 (m, 1H), 7.69(itt, 2H), 7.61-7.51 (m, 4H), 2.85 (s, 3H). LCMS: (M+H+) 403.1, (M+Na+) 425.0.

Example 17: /V-(6-Qxo-2-phenvl-5.6-dihvdro-1H-f1.2idiazepinoî4.5.6-ccnindol-8-vl1-2-phenvl- propionamide

HN-N

Préparation of example 17 from the title compound of Example 7(15 mg, 0.054 mmol), 2-phenyl-propionic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/v;/V'-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in/V,W-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (1:1 ethyl acetate: hexane), also in an analogous manner, followed by diethylether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.1H-NMR (de-DMSO): δ 12.08 (s, 1H), 10.33 (s, 1H), 10.21 (s, 1H), 8.16 (s, 1H), 7.64 (m, 3H), 7.59(m, 2H), 7.55 (m, 2H), 7.43 (m, 2H), 7.37 (m, 2H), 7.32 (m, 1H), 3.31 (quart., 1H), 1.45 (d, 3H).LCMS: (M+H+) 409.1, (M+Na+) 431.1.

Example 18: N-(6-Oxo-2-phenvl-5,6-dihvdro-1 H-Î1.21diazepinot4.5,6-cdlindol-8-vl)-2-phenoxv- acetamide

HN-N

Préparation of example 18 from the title compound of Example 7 (15 mg, 0.054 mmol), phenoxy-acetic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1- 013017 88 yl)-/V,/V,/V’W’-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (1:1 ethyl acetate:hexane increasing to 100% ethyl acetate), also in ananalogous manner, followed by diethyl ether trituration afforded the title compound (4.5 mg, 0.011 5 mmol) as a yellow powder in 20% yield. 1H-NMR (de-DMSO): δ 12.13 (s, 1H), 10.36 (s, 1H), 10.26 (s, 1H), 8.16 (s, 1H), 7.73 (m, 1H), 7.66(m, 2H), 7.57 (m, 2H), 7.51 (m, 2K), 7.31 (m, 2H), 7.03 (m, 3H), 4.71 (s„ 2H). LCMS: (M+H+) 411.0, (M+Na+) 433.1.

Example 19: Methvl-[(6-oxo-2-phenvl-5.6-dihvdro-1 H-fl ,2idiazepinof4.5,6-cc/lindol-8-vlcarbamovD- 10 methyll-carbamic acid ferf-butyl ester

Préparation of example 19 from the title compound of Example 7 (hydrochloride) (18 mg, 0.065mmol), (ferf-butoxycarbonyl-methyl-amino)-acetic acid (12 mg, 0.065 mmol), triethylamine (0.012mL, 0.085 mmol), and 0-(7-azabenzotriazol-1-yI)-/V,/V,/V',/V’-tetramethyluronium 15 hexafluorophosphate (27 mg, 0.072 mmol) in CH2CI2 (0.5 mL) and Λ/,/V-dimethylformamide (0.5mL) was carried out analogously to Example 11. Silica gel chromatography (10:9:1hexane:CH2CI2:methanol), also in an analogous manner, followed by diethyl ether triturationafforded the title compound (28 mg, 0.063 mmol) as a yellow powder in 96% yield. 1H NMR (CDCb): δ 9.11 (br s, 1H), 8.38 (br s, 2H), 7.62-7.46 (m, 7 H), 7.43 (s, 1H), 4.02 (s, 2H), 20 3.03 (s, 3H), 1.50 (s, 9H). LCMS: (M+H+) 448.1, (M+Na+) 470, (M-H) 446.1.

Example 20: 2-Methvlamino-/V-(6-oxo-2-phenvl-5.6-dihvdro-1H-H .2ldiazepinof4.5,6-cdlindol-8-vl)- methyll-acetamide: compound with trifluoro-acetic acid

25 The title compound of Example 19 (19 mg, 0.042 mmol) in CH2CI2 (0.65 mL) was treated withtrifluoroacetic acid (0.45 mL) and allowed to stir for 0.5 hours. The volatile components wereremoved under vacuum, and diethyl ether was added and evaporated three times to give the titleCompound (19 mg, U.U4I mmol) as a yelluw, uianyc puwUcr in 90% yield. 1H NMR (drmethanoi): δ 8.15 (s, partially exchanged), 7.68-7.52 (m, 8H), 4.00 (s, 2H), 2.80 (s, 30 3H). LCMS: (M+H+) 348.2. 013017

Example 21 : /V-(6-Oxo-2-phenvl-5.6-dihvdro-1/7-f1,2ldiazepino[4,5.6-cdlindol-8-vl)-butvramide

HN-N \\ 89

Préparation of example 21 from the title compound of Example 7 (hydrochloride) (22 mg, 0.080mmol), n-butyric acid (0.007 mL, 0.080 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,W’,/V-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) inCH2CI2 (0.3 mL) and W,/V-dimethylformamide (0.3 mL) was carried out analogously to Example11. Silica gel chromatography (10:9:1 hexane:CH2CI2:methanol followed by 9:5:1CH2CI2:hexane:methanol), also in an analogous manner, afforded the title compound (14 mg,0.04 mmol) as a yellow powder in 50% yield. 1H NMR (de-DMSO): 5. 12.05 (s, 1H, exchanges), 10.22 (s, 1H, exchanges), 10.00 (s, 1H,exchanges), 8.15 (s, 1H), 7.39-7.71 (m, 7H), 2.30 (m, 2H)1, 1.67 (m, 2H)2, 0.95 (m, 3H)1. 1Becomes triplet upon DCI addition, 2 Becomes quartet upon DCI addition. LCMS: (M+H+) 347.1, (M+Na+) 369.1.

Example 22: /V-(6-Oxo-2-phenvl-5,6-dihydro-1 H-Î1,21diazepinoI4.5.6-cdlindol-8-vl)-nicotinamide

HN-N

Préparation of example 22 from the title compound of Exampie 7 (hydrochloride) (21 mg, 0.076mmol), nicotinic acid (7 mg, 0.076 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-W,A/,/V’,/V-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) inCH2CI2 (0.3 mL) and N,W-dimethylformamide (0.3 mL) was carried out analogously to Example11. Silica gel chromatography (9:1 CH2CI2:methanol), also in an analogous manner, afforded thetitle compound (20 mg, 0.052 mmol) as a yellow powder in 69% yield. 1H NMR (d6-DMSO): δ. 12.18 (s, 1H, exchanges), 10.59 (s, 1H, exchanges), 10.38 (s, 1H,exchanges), 9.17(s, 1H), 8.80 (s, 1H, partially obscurred, with fine splitting), 8.40-8.26 (m, 2H),7.91 (S, 1H), 7.73-7.65 (m, 2H), 7.62-7.47 (m, 5H). 1H NMR (de-DMSO/DCI): δ. 9.44 (s, 1H), 9.10 (d, 1H, J = 5.0 Hz), 9.00 (d, 1H, J = 9.5), 8.32 (s,1H), 8.15 (dd, 1H, J = 7.0, 7.5 Hz ), 7.92 (s, 1H), 7.73 (s, 1H, overlapping), 7.68 (s, 1H,overlapping), 7.64-7.5U (m, 4M). LCMS: (171+^)382.1, (M+Na+) 404.1. 013017

Example 23: 2-Methvi-A/-(6-oxo-2-phenvl-5.6-dihvdro-1A/-f1,21diazepinof4.5,6-co1indol-8-vl)- benzamide 90

HN—N

Préparation of example 23 from the title compound of Example 7 (hydrochloride) (22 mg, 0.08mmol), 2-methyl-benzoic acid (11 mg, 0.08 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V’,/V’-tetramethyluronium hexafluorophosphate (33 mg, 0.088 mmol)in CH2CI2 (0.3 mL) and W,A/-dimethylformamide (0.3 mL) was carried out analogously to Example11. Silica gel chromatography (8:5:2 CH2CI2:hexane:methanol), also in an analogous manner,afforded the title compound (23 mg, 0.058 mmol) as a yellow powder in 73% yield. 1H NMR (de-DMSO): δ 12.11 (s, 1H, exchanges), 10.42 (s, 1H, exchanges}, 10.34 (s, 1H,exchanges), 8.24 (s, 1H), 7.88 (s, 1H), 7.71-7.65 (m, 2H), 7.63-7.45 (m, 3H), 7.43-7.35 (m, 2H),7.34-7.25 (m, 3H), 2.4 (s, 3H). LCMS: (M+H+) 395.1, (M+Na+) 417.0.

Example 24: A/-(6-Oxo-2-phenvl-5.6-dihvdro-1 <4-11,2ldiazepinof4.5.6-cdlindol-8-vl)-benzamide

HN—N

Préparation of example 24 from the title compound of Example 7 (hydrochloride) (23 mg, 0.082mmol), benzoic acid (11 mg, 0.09 mmol), triethylamine (0.016 mL, 0.115 mmol), and O-(7-azabenzotriazol-1-yl)-N,/\/,/V’,W-tetramethyluronium hexafluorophosphate (34 mg, 0.090 mmol) inCH2CI2 (0.3 mL) and W,W-dimethylformamide (0.3 mL) was carried out analogously to Example11. Silica gel chromatography (10:9:1 hexane:CH2CI2:methanol followed by 8:5:2CH2CI2:hexane:methanol), also in an analogous manner, afforded the title compound (20 mg,0.053 mmol) as a yellow powder in 64% yield. 1H NMR (d6-DMSO): δ 12.13 (s, 1H), 10.41 (s, 1H), 10.35 (s, 1H), 8.32 (s, 1H), 8.03 (d, 2H, J = 8Hz), 7.94 (s, 1H), 7.70 (s, 1H, overlapping), 7.67 (s, 1H, overlapping), 7.63-7.48 (m, 7H). LCMS: (M+H+) 381.î, (M+Na+) 403.1. 013017

Example 25: ZV-(6-Oxo-2-phenvl-5,6-dihvdro-1 H-f1,21diazepinoî4.5,6-cd1indol-8-vl)-2-phenvl- acetamide 91

Préparation of example 25 from the title compound of Example 7 (hydrochloride) (20 mg, 0.072 5 mmol), phenyl-acetic acid (11 mg, 0.08 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V’,A/-tetramethyluronium hexafluorophosphate (30 mg, 0.080 mmol) inCH2CI2 (0.3 mL) and /V,/V-dimethylformamide (0.3 mL) was çarried out analogously to Example11. Silica gel chromatography (8:5:2 CK2CI2:hexane:methanol), also in an analogous manner,afforded the title compound (27 mg, 0.058 mmol) as a yellow powder in 95% yield. 10 ’H NMR (d6-DMSO): δ 12.08 (s, 1H, exchanges), 10.31 (s, 2H, exchanges), 8.18 (s, 1H), 7.72-7.62 (m, 3H), 7.60-7.45 (m, 4H), 7.41-7.21 (m, 5H), 3.68 (S, 2H). LCMS: (M+H+) 395.1, (M+Na+) 417.1. 15 Example 26: /V-(6-Oxo-2-phenvl-5,6-dihydro-1/-/-H ,2ldiazepinof4.5.6-cc/lindol-8-yB-2-piperazÎn-1- yl-acetamide Pz-trifluoroacetic acid Sait

To a suspension of the title compound of Example 27 in dichioromethane (0.3 M, 0.6 mL), wasadded trifluoroacetic acid (0.3 M, 0.6 mL). The réaction mixture was stirred at 22 °C for 0.5 hours 20 and concentrated under reduced pressure. The solid was triturated with dichioromethane (3.0mL), collected by filtration, and washed with diethyl ether (5.0 mL) to afford the title compound(9.8 mg) in 95% yield. 1H-NMR (ds-DMSO): δ 12.09 (s, 1H), 10.36 (s, 1H), 9.98 (s, 1H), 8.53 (bs, 2H), 8.16 (d, 1H, J =1.6 Hz), 7.66 (m, 2H), 7.69-7.48 (m, 7H), 3.32 (s, 2H), 3.20 (m, 4H), 2.82 (m, 4H). 25 HRMS: (M+H+) calcd for C^gNeOs, 403.1882, found 403.1902. 013017

Example 27: 4-f(6-Oxo-2-phenyl-5,6-dihydro-1 /7-[1,2ldiazepinof4,5,6-ccnindol-8-vlcarbamovl')- methyll-piperazine-l-carboxylic acid terf-butvl ester 92

10

Préparation of example 27 from the title compound of Example 7 (0.025g, 0.09 mmol), 4-carboxymethyl-piperazine-1-carboxylic acid ferf-butyl ester (0.044 g, 0.18 mmol), triethylamine(0.05 mL, 0.4 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/V,/V',/V-tetramethyluroniumhexafluorophosphate (38 mg, 0.1 mmol) and Λ/,/V-dimethylformamide (0.05 M, 1.8 mL) wascarried out analogously to Example 11. Silica gel chromatography (95:5 CH2CI2/methanol), also inan analogous manner, afforded the title compound (15 mg) as a yellow powder in 33% yield.1H-NMR (d6-DMSO): δ 12^07 (s, 1H), 10.34 (s, 1 H), 9.92 (s, 1H), 8.17 (s, 1H), 7.69-7.64 (m, 3H),7.61-7.54 (m, 2H), 7.52-7.47 (m, 2H), 3.40 (m, 4H), 3.29 (m buried, 4H), 3.18 (s, 2H). HRMS: (M+H+) calcd for C29H31N6O4, 503.2407, found 503.2407. 15

The starting material 4-Carboxymethyl-piperazine-1-carboxylic acid ferf-butyl ester was preparedas follow:

y-V-OEt (Bog)2O, Et3N HN N—' - —f CH2CI2, rt, 94%

O /—\ V-OEt*- BocN N—'

5% KOH, THF O-rt, 37%

BocN V_/ 27(a) 27(b)

Step 1. Préparation of 4-Methoxycarbonylmethyl-piperazine-1-carboxylic acid ferf-butylester 27(a)

Piperazin-1-yl-acetic acid ethyl ester (2.84 g, 15.7 mmol), triethylamine (7.6 mL, 55.0 mmol) and20 di-ferf-butyl dicarbonate (4.45 g, 20.4 mmol) were stirred in CH2CI2 (0.3 M, 55 mL) at 22 °C for 24hours, The volatiles were removed zn vacuo and silica gel chromatography (60:40 ethyl acetate/hexanes), afforded Intermediate 27(a) (4.01 g) in 94% yield. 1H-NMR (de-DMSO): δ 4.08 (q, 2H, J = 7.1 Hz), 3.35-3.21 (m, 6H), 2.52-2.41 (m, 4H), 1.39 (s,9H), 1.18 (t, 7.1 Hz). 25 13C-NMR (d6-DMSO): δ 170.2, 154.2, 79.1, 60.2, 58.6, 52.0, 28.4, 14.5.

Step 2. Préparation of 4-Carboxymethyl-piperazine-1-carboxylic acid ferf-butyl ester 27(b)

Intermediate 27(a) (3.6 g, 13.2 mmol) and a 5% aqueous KOH solution (90 mL, 80.0 mmol) werestirred in tetrahydrofuran (30 mL, 0.44 M) at 22 °C for 2 hours. The volatiles were removed invacuo and treatment with strongly acidic Dowex-50™ (WX8-200), elution with ammonium 013017 93 hydroxide (1.0 N), and treatment with Amberlite™ CG-50 afforded Intermediate 27(b) (1.2 g) in37% yield. 1H-NMR (de-DMSO): δ 3.35-3.31 (m, 4H), 3.21 (s, 2H), 2.52-2.41 (m, 4H), 1.39 (s, 9H).

Example 28: 2-Cvclohexvi-A/-f6-oxo-2-phenvl-5.6-dihvdro-1W1.2ldiazepino|4,5.6-cdlindol-8-vh- acetamide

Préparation of example 28 from the title compound of Example 7 (0.025g, 0.09 mmol),Cyclohexyl-acetic acid (0.015g, 0.11 mmol), triethylamine (0.05 mL, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-A/,A/,A/’,A/'-tetramethyiuronium hexafluorophosphate (38 mg, 0.1 mmol) and/V,W-dimethylformamide (0.05 M, 1.8 mL) was carried out analogously to Example 11. Silica gelchromatography (95:5 CH2CI2/methanol) also in an analogous manner followed by diethyl etbertrituration afforded the title compound (13 mg) as a yellow powder in 36% yield. 1H-NMR (de-DMSO): δ 12.03 (s, 1H), 10.32 (s, 1H), 9.99 (s, 1H), 8.17 (s, 1H), 7.68-7.45 (m, 7H),2.20 (d, 2H, J= 7.0 Hz), 1.86-1.58 (m, 6H), 1.31-1.10 (m, 3H), 1.10-0.91 (m, 2H). HRMS: (M+H+) calcd for C24H25N4O2,401.1978, found 401.1987.

Example 29: 4-(6-Oxo-2-phenvl-5.6-dihvdro-1 H-11.2ldiazepinoi4.5,6-cdlindol-8-vlcarbamovl’)- piperidine-1-carboxvlic acid terf-butvl ester

Préparation of example 29 from the title compound of Example 7 (hydrochloride) (22 mg, 0.07mmol), piperidine-1,4-dicarboxylic acid mono-fert-butyl ester (19 mg, 0.084 mmol), triethylamine(0.015 mL, 0.105 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,/V’,/V-tetramethyluroniumhexafluorophosphate (32 mg, 0.084 mmol) in CH2CIZ (0.3 mL) and Λ/,/V-dimethylformamide (0.3mL) was carried out analogously to Example 11. Silica gel chromatography (8:5:2CH2CI2:hexane:methanol), also in an analogous manner, afforded the title compound (24 mg,0.049 mmol) as a yellow powder in 70% yield. 1H NMR (d6-DMSO): 12.09 (s, 1H), 10.38 (s, 1H), 10.12 (s, 1H), 8.17 (s, 1H), 7.70-7.64 (m, 3H),7.62-7.54 (m, 2H), 7.53-7.49 (m, 2H), 4.01 (br d, 2H, J = 12.06 Hz;, z.tse-z.zz (m, zri), i.e ι (Di a,2H, J = 13.00 Hz), 1.58-1.44 (m, 2H), 1.42 (s, 9H), 1.40 (m, 1H, partiaily obscured). LCMS: (Μ-H)’ 486.2. 013017

Example 30: 4-f(6-Qxo-2-phenvl-5,6-dihvdro-1/-/-n .21diazepinof4,5.6-cdlindol-8-vlcarbamovh- methvn-piperidine-1-carboxvlic acid terf-butvl ester 94

Préparation of example 30 from the title compound of Example 7 (hydrochloride) (22 mg, 0.075 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid ferî-butyl ester (20 mg, 0.084 mmol),triethylamine (0.015 mL, 0.105 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/V,/V’,/V-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2CI2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gelchromatography (8:5:2 CH2CI2:hexane:methanol), also in an analogous manner, afforded the title 10 compound (35 mg, 0.070 mmol) as a yellow powder in 100% yield. ’H NMR (d6-DMSO): 12.08 (s, 1H), 10.38 (s, 1H), 10.09 (s, 1H), 8.19 (s, 1H), 7.70-7.46 (m, 7H),3.93 (br d, 2H, J = 12.24 Hz), 2.81-2.66 (m, 2H), 2.27 (d, 2H, J = 7.16 Hz), 1.96 (br s, 1H), 1.67(brd, 2H, J= 13.94 Hz), 1.40 (s, 9H), 1.17-1.01 (m, 2H). LCMS: (M+Na+) 524.2, (M-H)‘ 500.1. 15 Example 31: Piperidine-4-carboxvlic acid (6-oxo-2-phenvl-5,6-dihvdro-1H-H,21diazepinof4.5.6-cdlindol-8-vD-amide; compound with trifluoro-acetic acid

Préparation of example 31 from the title compound of Example 29 (20 mg, 0.041 mmol) and 45%TFA in CH2CI2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous 20 manner, afforded the title compound (20 mg, 0.040 mmol) as a yellow powder in 97% yield. 1H NMR (d4-methanol): 8.03 (s, 1H), 7.56-7.31 (m, 7H), 3.43-3.32 (m, 2H), 3.01-2.90 (m, 2H),2.61 (m, 1H)r 2.04 -1.78 (m, 4H). LCMS: (M+H+) 388.1

Example 32: /V-(6-Oxo-2-phenyl-5,6-dihydro-1 H-f1.21diazepinoi4,5,6-cdlindol-8-vl)-2-piperidin-4-vl- 25 acetamide; compound with trifluoro-acetic acid

013017 95

Préparation of example 32 from the title compound of Example 30 (31 mg, 0.062 mmol) and45% TFA in CH2CI2 (1 mL) was carried out analogously to Example 20. Isolation, aiso in ananalogous mariner, afforded the title compound (29 mg, 0.056 mmol) as a yellow powder in 91%yield. 1H NMR (d4-methanol): § 8.20 (s, 1.H), 7.70-7.50 (m, 7H), 3.50-3.40 (m, 2H, partially obscurred),3.10 (dd, 2H, J = 9.0, 9.2 Hz), 2.45 (d, 2H, J = 7.2 Hz), 2.25 (br m, 1H), 2.0-2.11 (m, 2H), 1.68-1.45 (m,2H). LCMS: (M+H+) 402.2

Example 33: ferf-butvl f1S)-1-cvclohexvl-2-oxo-2-f(6-oxo-2-phenvl-5.6-dihvdro-1/-/- H.21diazepinol4,5.6-cdlindol-8-v0amino1ethvlcarbamate

HN—N

BocHN

Préparation of example 33 from the title compound of Example 7 (35 mg, 0.13 mmol), (2S)-[(fe/t-butoxycarbonyl)amino](cyclohexyl)ethanoic acid (39 mg, 0.15 mmol), triethylamine (0.073 mL,0.52 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,W',/V-tetramethyluronium hexafluorophosphate(58 mg, 0.15 mmol) in W,/V-dimethylformamide (2.0 mL) was carried out analogously to Example11 except that after 24 hours additional (2S)-[(fert-butoxycarbonyl)amino](cyclohexyl)ethanoic acid(17 mg, 0.065 mmol) and O-(7-azabenzotriazol-1-yl)-W,/V,/V',/V-tetramethyluroniumhexafluorophosphate (25 mg, 0.065 mmol) were added to drive the reaction to completion. Silicagel chromatography (1:1 ethyl acetate;hexane), also in an analogous manner, followed by diethylether triturationafforded the title compound (45 mg, 0.087 mmol) as a yellow powder in 67% yield.1H-NMR (d6-DMSO): δ 12.08 (s, 1H), 10.38 (s, 1H), 10.13 (s, ΊΗ), 8.14 (s, 1H), 7.71-7.44 (m, 6H),6.90 (m, 1H), 3.95 (m, 1H), 1.78-1.44 (m, 5H), 1.43-1.24 (m, 10H, contains singletat 1.39), 1.23-1.02 (m, 5H). LCMS: (M+H)'514.1. .

Example 34: (2S)-2-amino-2-cvclohexvl-/\/-f6-oxo-2-phenvl-5,6-dihvdro-1H-f1,2idiazepinor4.5.6- cdlindol-8-vl)ethanamide trifluoroacetate

HN-N TFA nh2 013017 96

Préparation of example 34 from the title compound of Example 33 (40 mg, 0.078 mmol), and 1:1TFA/CH2CI2 (5 mL) was carried out analogously to Example 20. Isolation, also in an analogousmanner, included a further trituration with methanol/diethyl ether and afforded the title compound(10 mg, 0.019 mmol) as an orange/yellow powder in 24% yield. 5 1H NMR (d6-DMSO): δ 12.19 (s, 1H), 10.60 (s, 1 H), 10.44 (s, 1H), 8.25 (br s, 3H), 8.11 (s, 1H),7.71-7.46 (m, 7H), 3.69 (m, 1H), 1.93-1.52 (m, 6H), 1.29 -0.97 (m, 5H). LCMS: (M+H+) 415.1.

Example 35: 3-Fluoro-A/-(6-oxo-2-phenvl-5.6-dihvdro-1/-/-f1.2)diazepinof4.5.6-cdlindol-8-vl)- benzamide

Préparation of example 35 from the title compound of Example 7 (0.025g, 0.09 mmol), 3-Fluoro-benzoic acid (0.015g, 0.11 mmol), triethylamine (0.05 mL, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-/V,W,/V’,/V’-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol) and N,N-dimethylformamide (0.05 M, 1.8 mL) was carried out analogously to Example 11. Silica gel 15 chromatography (95:5 CH2CI2/methanol), also in an analogous manner, afforded the titlecompound (15 mg) as a yellow powder in 42% yield. 1H-NMR (d6-DMSO): δ 12.18 (s, 1H), 10.47 (s, 1H), 10.40 (s, 1H), 8.31 (d, 1H, J= 1.3 Hz), 7.92(d, 1H, J= 1.5 Hz), 7.90-7.81 (m, 2H), 7.72-7.41 (m, 8H). HRMS: (M+H+) calcd for CzaHieN^F, 399.1257, found 399.1257. 20 Example 36: /V-i6-Oxo-2-phenvl-5.6-dihvdro-1H-f1.21diazepinor4.5.6-cd1indol-8-vl)-4-phenvl- butvramide

Préparation of example 36 from the title compound of Example 7 (0.030g, 0.11 mmol), 4-Phenyl-butyric acid (0.027g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)- 25 /V,W,/V'/\/-tetrarnethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N-dimethylformamido (0.05 M, 2.0 mL) «ras narriad ni it analogously to Examole 11. Silica Cielchromatography (95:5 CH2Cl2/methanol) afforded the title compound (15 mg) as a yellow powderin 33% yield; 013017 97 1H-NMR (de-DMSO): δ 12.06 (s, 1H), 10.35 (s, 1H), 10.06 (s, 1H), 8.18 (d, 1H, J= 1.5 Hz), 7.69-7.46 (m, 7H), 7.33-7.16 (m, 5H), 2.64 (dd, 2H, J= 7.4, 7.0 Hz), 2.35 (m, 5H), 1.97-1.86 (m, 2H).HRMS: (M+H*) calcd for C26H23N4O2, 423.1821, found 423.1826.

Anal. Calcd. for C26H22N4O2 · 0.2 H2O: C, 73.29; H, 5.30; N, 13.15. Found: C, 73.33; H, 5.28; N,5 13.23.

Example 37: 1-Methyl-piperidine-4-carboxylic acid (6-oxo-2-phenvl-5.6-dihvdro-1/7- f1.21diazepinoF4,5,6-cdlindol-8-yl)-amide; 2.2.2-trifluoro-acetic acid sait

Préparation of example 37 from the title compound of Example 7 (0.030g, 0.11 mmol), 1-Methyl- 10 piperidine-4-carboxylic acid (0.023g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-/V,A/,/V',/V’-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) andAF,W-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. HPLCpurification afforded the title compound (23 mg) as a yellow powder in 41% yieid. 15 1H-NMR (ds-DMSO): δ 12.10 (s, 1H), 10.39 (s, 1H), 10.23 (s, 1H), 9.17 (bs, 1H), 8.12 (d, 1H, J =1.5 Hz), 7.69-7.47 (m, 7H), 3.05-2.93 (m, 2H), 2.80 (d, 3H), 2.65-2.48 (buried m, 1H), 2.10-2.01(m, 2H), 1.92-1.80 (m, 2H). HRMS: (M+H+) calcd for C23H24N5O2,402.1930, found 402.1937.

Example 38: /V-(6-Oxo-2-phenyl-5.6-dihydro-1H-F1.2FdiazepinoF4.5.6-cd1indol-8-yl)-3-phenvl- 20 propionamide

Préparation of example 38from the title compound of Example 7 (0.030g, 0.11 mmol), 3-Phenyl-propionic acid (0.025g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-/V,/V,A/’/V-tetramethyiuronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N- 25 dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gelchromatoaraphy (95:5 CH2CI2/methanol) afforded the title compound (15 mg) as a yellow powderin 34% yieid. 013017 98 1H-NMR (d6-DMSO): δ 12.09 (s, 1H), 10.38 (s, 1H), 10.36 (s, 1H), 10.13 (s, 1H), 8.15 (d, 1H, J =1.5 Hz), 7.68-7.46 (m, 11 H), 7.31 (d, 2H, J = 8.4 Hz), 7.24 (d, 1 H, J =8.2 Hz), 3.65 (s, 2H), 3.45(s, 2H). HRMS: (M+H+) calcd for C25H21N4O2, 409.1665, found 409.1683. 5 Example 39: 6-Oxo-2-phenvl-5.6-dihvdro-1/-/-f1.2ldiazepinof4,5.6-cdlindole-8-carboxvlic acid methvl ester

Dioxane, rt, 53%

NH2NH2.H2O, AcOH ->.

MeOH, reflux, 72%

10

Step 1. Préparation of 4-bromo-5-nitroisophtiiaIic acid 39(a)

To a 3-L 4-neck round-bottomed flask equipped with a mechanical stirrer, thermometer, 250-mLaddition funnel and charged with concentrated H2SO4 (577 mL), was added 4-bromoisophthalicacid (75.0 g, 306 mmol). The white suspension was cooled to ice-bath température and a nitratingreagent (pre-prepared by the careful addition of H2SO4 (169 mL) to HNO3 (107 mL)) was slowlyadded while maintaining an internai reaction température of less than 15 °C. When addition wasoomploto, the ioe-hoth urac remnwod and tha ri ispAnsinn stirred overnioht at room température.After approximately 14 hours, the flask was placed in an ice-bath and crushed ice was added toquench the excess nitrating reagent while maintaining an internai température less than 40 °C.The cream-colored suspension was filtered, and the solids were collected by filtration and washed 15 013017 99 with a small volume of ice-cold water. The solids were dissolved in methanol and the volatilecomponents were evaporated. The resulting solids were dried at 60 °C in a vacuum ovenovernight to afford Intermediate 39(a) (79.6 g) in 87% yield. 1H NMR (d4-methanol): δ 8.47 (d, 1H, J= 1.8 Hz), 8.39 (d, 1H, J= 1.8 Hz). LCWIS: (M-H) 289.

Step 2. Préparation of Dimethyl 4-bromo-5-nitroisophthalate 39(b)

To a solution of Intermediate 39(a) (77.6 g, 267 mmol) in methanol (500 mL) was addedconcentrated H2SO4 (10 mL). The reaction flask was heated in an oil bath at reflux with stirring forapproximately 8 hours at which point LC/MS analysis indicated consumption of starting material.The mixture was allowed to cool to room température and white solids began to crystallize in theflask. After sitting overnight, the crystals were collected by filtration and washed with water untilthe pH of the filtrate was neutral. The crystals (51.9 g) were dried in an Abderhalden dryingapparatus over refiuxing acetone. The mother liquor was concentrated to provide a second crop(7.58 g) which was combined with the first to afford Intermediate 39(b) (59.4 g) in 70% yield. 1H NMR (ds-DMSO): δ 8.62 (s, 1H), 8.45 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H).

Step 3. Préparation of Dimethyl 5-nitro-4-(phenylethynyl)isophthalate 39(c) A flask containing 1,4-dioxane (16 mL) was purged with nitrogen. Cul (0.12 g, 0.628 mmol) andbis(benzonitrile)dichloropalladium(ll) (0.361 g, 0.942 mmol) were added in portions. Tri-fezf-butylphosphine (7.83 mL, 1.88 mmol) was added as a 0.24 M solution in 1,4-dioxane via syringe.The solution was allowed to stir for approximately 5 min at which point diisopropylamine (2.65 mL,18.9 mmol) was added via syringe. Intermediate 39(b) (5.00 g, 15.7 mmol) was added in one solidportion followed by phenylacetylene (2.08 mL, 18.9 mmol). A precipitate formed immediately. Thereaction was capped and stirred at room température overnight. The mixture was filtered throughdiatomaceous earth which was subsequently washed with ethyl acetate to recover any trappedproduct. The combined filtrate and washings were concentrated and dissolved in a minimalamount of hot ethyl acetate. Hexane was added to recrystallize brown needles which werecollected by filtration and further washed with hexane. The needles (4.5 g) were dried in a vacuumoven at 60 ’C overnight. The mother liquor was concentrated and subjected to silica gelchromatography (10-30% ethyl acetate/hexanes) to yield an additional 1.2 g of a dark brown solidwhich was combined with the first batch to afford Intermediate 39(c) (5.7 g) in 53% yield. 1H NMR (CDCIa): § 8.73 (d, 1H, J = 1.5 Hz), 8.65 (d, 1H, J= 1.8 Hz), 7.61-7.64 (m, 2H), 7.37-7.46(m, 3H), 4.03 (s, 3H), 4.00 (s, 3H). LCMS: (M+H) 340.

Step 4. Préparation of Dimethyl 2-phenyl-1H-indole-4,6-dicarboxylate 39(d)

To Intermediate 39(c) (6.37 g, 18.8 mmol) was added anhydrous methanol (120 mL). To theresulting slurry was added Tin(ll) chloride (35.6 g, 188 mmol), and the reaction flask was refluxedfor 55 hours. Methanol was removed under reduced pressure and the resulting residue was 013017 100 suspended in a small volume of ethyl acetate. Dichloromethane was then added such that theresulting concentration was approximately 95% dichloromethane : 5% ethyl acetate. Thissuspension was then filtered through a short silica gel plug. The filtrate was concentrated andpurified twice by flash silica gel chromatography {5-40% ethyl acetate/dichloromethane) to obtain3.1 g of Intermediate 39(d) in 53% yield. 1H NMR (de-DMSO): 5 12.35 (s, 1H), 8.37 (s, 1 H), 8.28 (s, 1H), 7.98-8.00 (m, 2H), 7.47-7.60 (m,4H), 3.99 (s, 3H), 3.93 (s, 3H). LCMS: (M+H) 310.

Step 5. Préparation of Dimethyl 3-formyl-2-phenyl-1H-indole-4,6-dicarboxylate 39(e)

To a solution of Intermediate 39{d) (0.052 g, 0.17 mmol) in anhydrous ty/V-dimethylformamide (2mL) at room température was added POCI3 (0.2 mL, 2.1 mmol). The resulting violet solution wasstirred for 1 hour at room température. The mixture was poured into saturated aqueous sodiumcarbonate (15 mL) and extracted with ethyl acetate. The organic layer was dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (33% ethyl acetate/hexanes) togive Intermediate 39(e) (0.0404 g) in 71% yield. 1H NMR (d6-DMSO): ζ 13.00 (s, 1H), 9.95 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.85-7.75(m, 2H),7.70-7.55 (m, 3H), 3.90 (S, 3H), 3.86 (s, 3H). LCMS: (M+H) 338, (M-H) 336.

Step 6. Préparation of Title Compound: 6-Oxo-2-phenyl-5,6-dihydro-1/f- [1,2]diazepino[4,5,6-cd]indole-8-carboxylic acid methyl ester

To a solution of Intermediate 39(e) (1.39 g, 4.12 mmol) in anhydrous methanol (70 mL) wasadded anhydrous hydrazine (0.19 mL, 6.18 mmol). The mixture was refluxed overnight. Aftercooling, the yellow precipitate was collected by filtration and washed with ice-cold methanol. Afterdrying under vacuum at 60 °C overnight, the title compound (1.06 g) was obtained as a brightyellow solid in 72% yield. ’H-NMR (de-DMSO): δ 12.58 (s, 1H), 10.54 (s, 1H), 8.13 (d, 1H, J = 1.3 Hz), 8.07 (d, 1H, J = 1.3Hz), 7.77-7.67(m, 2H), 7.65-7.54 (m, 3H), 7.52 (s, 1H), 3.88 (s, 3H). LCMS: (M+H+) 320.3

Example 40: 3-Fluoro-2-methyl-A/-(6-oxo-2-phenvl-5.6-dihvdro-1 H-f 1.21diazepinof4.5.6-ccHindol-8- vl)-benzamide

F 013017 101

Préparation of example 40 from the title compound of Example 7 (0.030g, 0.11 mmol), 3-Fluoro-2-methyl-benzoic acid (0.025g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-A/,/V,/\/',/V-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) andΛ/,/V-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gelchromatography (95:5 CH2CI2/methanol) afforded the title compound (14 mg) as a yellow powderin 33% yield. 1H-NMR (de-DMSO): δ 12.15 (s, 1H), 10.55 (s, 1H), 10.39 (s, 1H), 8.23 (d, 1H, J = 1.5 Hz), 7.84(d, 1 H, J = 1.4 Hz), 7.72-7.48 (m, 6H), 7.39-7.27 (m, 3H), 2.31 (s, 3H). LCMS: (M-H+)411.0.

Example 41: 2-Fluoro-/V-(6-oxo-2-phenvl-5.6-dihydro-1 Β-Γ1,21diazepino[4,5,6-cdlindol-8-vl)-3- trifluoromethvl-benzamide

Préparation of example 41 from the title compound of Example 7 (0.1 g, 0.36 mmol), 2-Fluoro-3-trifluoromethyl-benzoic acid (0.113 g, 0.54 mmol), triethylamine (0.2 mL, 1.45 mmol), O-(7-azabenzotriazol-1-yl)-A/,A/,A/',/V'-tetramethyluronium hexafluorophosphate (0.207 g, 0.54 mmol)and Λ/,/V-dimethylformamide (0.1 M, 3.6 mL) was carried out analogously to Example 11, Silica gelchromatography (95:5 CH2CI2/methanol) afforded the title compound (0.147 g) as a yellow powderin 87% yield. 1H-NMR (de-DMSO): δ 12.20 (s, 1H), 10.81 (s, 1H), 10.43 (s, 1H), 8.24 (d, 1H, J = 1.5 Hz), 8.05-7.93 (m, 2H), 7.79 (d, 1 H, J = 1.4 Hz), 7.72-7.67 (m, 2H), 7.62-7.49 (m, 5H). HRMS: (M+H+) calcd for C24H15N4O2 F4,467.1131, found 467.1119.

Anal. Calcd. for C24H14N4O2F4 · 0.2 H2O: C, 61.33; H, 3.09; N, 11.92; F, 16.17. Found: C, 61.17;H, 3.09; N, 11.93; F, 16.65.

Example_42:_/V-(6-Qxo-2-phenyl-5.6-dihvdro-1 H-] 1.21diazepinof4.5,6-cd1indol-8-vl)-2- trifluoromethvl-benzam ide

Préparation of example 42 from the title compound of Example 7 (0.1 g, 0.36 mmol), 2-Trifluoromethyl-benzoic acid (0.103g, 0.54 mmol), triethylamine (0.2 mL, 1.45 mmol), O-(7-

102 azabenzotriazol-1-y))-A/,Z\/,/V',W-tetramethyluronium hexafluorophosphate (0.207 g, 0.54 mmol)and /V,A/-dimethylformamide (0.1 M, 3.6 mL) was carried out analogously to Example 11. Silica gelchromatography (95:5 CH2CI2/methanol) afforded the title compound (0.075 g) as a yellow powderin 46% yield. 5 1H-NMR (de-DMSO): δ 12.14 (s, 1 H), 10.71 (s, 1H), 10.40 (s, 1H), 8.17 (d, 1H, J = 1.4 Hz), 7.89-7.66 (m, 7H), 7.62-7.49 (m, 4H). HRMS: (M+H+) calcd for C24H16N4O2 F3, 449.1225, found 449.1223.

Example_43:_A/-(6-Qxo-2-phenvl-5.6-dihvdro-1/-/-f1.2ldiazepinoi4.5.6-cdlindol-8-vh-3- trifluoromethvl-benzamide

HN-N 10

Préparation of example 43 from the title compound of Example 7 (0.03 g, 0.11 mmol), 3-Trifluoromethyl-benzoic acid (0.031 g, 0.16 mmol), triethyiamine (0.078 mL, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-/V,A/,/V’,/V'-tetramethyluronium hexafluorophosphate (0.062 g, 0.11 mmol)and Λ/,/V-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica 15 gel chromatography (95:5 CH2CI2/methanol) afforded the title compound (0.030 g) as a yellowpowder in 61% yield. 1H-NMR (ds-DMSO): δ 12.20 (s, 1H), 10.62 (s, 1H), 10.42 (s, 1H), 8.39-8.30 (m, 3H), 7.98 (d, 1H,J =7.4 Hz), 7.91 (d, 1H, J = 1.6 Hz), 7.80 (dd, 1H, J= 7.7, 7,5 Hz), 7.69 (d, 2H, J = 7.2 Hz), 7.62- 7.48 (m, 4H). 20 HRMS: (M+H+) calcd for C24H16N4O2 F3, 449.1225, found 449.1229.

Example 44: 3-Chloro-/\/-(6-oxo-2-phenvl-5.6-dihvdro-1 H-f1.21diazepinor4.5.6-ccflindol-8-vh- benzamide

HN-N

Préparation of example 44 from the title compound of Example 7 (0.03 g, 0.11 mmol), 3- 25 Chloromethyl-benzoic acid (0.025 g, 0.16 mmol), triethyiamine (0.078 mL, 0.43 mmol), O-(7- azabenzotriazol-1-yl)-/V,/V,/V’,/V’-tetramethyluronium hexafluorophosphate (0.062 g, 0.11 mmol) and ty/V-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica 013017 103 gel chromatography (95:5 CH2CI2/methanol) afforded the title compound (0.015 g) as a yellowpowder in 33% yield. 1H-NMR (d6-DMSO): δ 12.18 (s, 1H), 10.50 (s, 1H), 10.41 (s, 1H), 8.32 (d, 1H, J= 1.5 Hz), 8.09(s, 1H), 7.98 (d, 1H, J= 7.8 Hz), 7.91 (d, 1H, J= 1.6 Hz), 7.72-7.65 (m, 3H), 7.62-7.47 (m, 5H).HRMS: (M+H*) calcd for C23H16N4O2CI, 415.0962, found 415.0981.

Example 45: (1R.2RÏ-2-Phenvl-cyclopropanecarboxvlic_acid_(6-oxo-2-phenvl-5,6-dihvdro-1 H- f1.21diazepinof4.5.6-ct/lindol-8-vl)-amide; and (1S.2S)-2-Phenvl-cvclopropanecarboxvlic_acid_(6-oxo-2-phenvl-5,6-dihydro-1H- f1.21diazepinof4,5.6-cdlindol-6-vl)-amide

HN-N

Préparation of example 45 from the title compound of Example 7 (30 mg, 0.11 mmol), + trans-2-phenyl-1-cyclopropanecarboxylic acid (26 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol),and 0-(7-azabenzotriazol-1-yi)-/V,W,A/)W-tetrarriethyluronium hexafluorophosphate (62 mg, 0.16mmol) in W,A/-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gelchromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by triturationwith ethyl acetate / diethyl ether afforded the title compound (6.5 mg, 0.015 mmol) (mixture oftrans diastereomers) as a yellow powder in 14% yield. 1H-NMR (de-DMSO): δ 12.09 (s, 1H), 10.44 (s, 1H), 10.37 (s, 1H), 8.17 (s, 1H), 7.71-7.44 (m, 7H),7.35-7.25 (m, 2H), 7.24-7.10 (m, 3H), 2.39 (m, 1H), 2.10 (m, 1H), 1.52 (m, 1H), 1.38 (m, 1H).LCMS: (M+H)'419.1.

Example 46: 2-f3-ChlorophenvB-/V-(6-oxo-2-phenvl-5.6-dihvdro-1 H-11.21diazepinof4.5.6-cd1indol- 8-vhacetamide

HN-N

Préparation of example 46 from the title compound of Example 7 (30 mg, 0.11 mmol), (3-chlorophenyl)acetic acid (28 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-W,W,W’,A/’-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) inW,/V-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gel 013017 104 chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by methanoltrituration afforded the title compound (6.5 mg, 0.015 mmol) as a yeliow powder in 14% yield.1H-NMR (d6-DMSO): δ 12.10 (s, 1H), 10.39 (s, 1H), 10.17 (s, 1H), 8.16 (s, 1H), 7.70 -7.18 (m,11 H), 3.69 (s, 1 H), 3.50 (s, 1 H). LCMS: (M+H)'427.1.

Example 47: A/-(6-Oxo-2-phenyl-5.6-dihvdro-1H-i1,21diazepinoi4.5.6-cd1indol-8-vl)-4-thien-2- vlbutanamide

HN-N

Préparation of example 47 from the title compound of Example 7 (30 mg. 0.11 mmol), 4-thien-2-ylbutanoic acid (24 mg, 0.16 mmol), triethyiamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-/V,A/,W',A/’-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) inΛ/,ΛΑ-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gelchromatography (3% methanol in CH2CI2 increasing to 6% methanol in CH2CI2), also in ananalogous manner, followed by methanol trituration afforded the title compound (6.5 mg, 0.015mmol) as a yeliow powder in 14% yield. 1H-NMR (de-DMSO): δ 12.07 (s, 1H), 10.38 (s, 1H), 10.09 (s, 1H), 8.18 (s, 1 H), 7.69-7.61 (m, 3H),7.60-7.53 (m, 2H), 7.52-7.45 (m, 2H), 7.33 (m, 1H), 6.96 (m, 1H), 6.89 (m, 1H), 2.86 (t, 2H, J =7.53 Hz), 2.40 (t, 2H, J= 7.35 Hz), 2.02 -1.89 (m, 2H). LCMS: (M+H)'427.1.

Example 48: 1-Acetvl-/V-(6-oxo-2-phenvl-5.6-dihvdro-1H-f1.21diazepinof4.5.6-ccf|indol-8- vl)piperidine-4-carboxamide

Préparation of example 48 from the title compound of Exampie 7 (30 mg, 0.11 mmol), 1-acetylpiperidine-4-carboxylic acid (28 mg, 0.16 mmol), triethyiamine (0.076 mL, 0.55 mmol), andO-(7-azabenzotriazol-1-yl)-ZV,A/,/V’,/V-tetramethy)uronium hexafluorophosphate (62 mg, 0.16mmol) in /V,/V-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gelchromatography (3% methanol in CH2CI2 increasing to 6% methanol in CH2CI2), also in an 013017 105 analogous manner, followed by methanol trituration afforded the title compound (12 mg, 0.028mmol) as a yellow powder in 25% yield. 1H-NMR (d6-DMSO): δ 12.07 (s, 1H), 10.37 (s, 1H), 10.10, s, 1H), 8.17 (s, 1H), 7.72-7.43 (m, 7H),4.41 (d, 1H, J = 15.07 Hz), 3.87 (d, 1H, J = 14.13 Hz), 3.07 (t, 1H, J = 12.81 Hz), 2.65-2.53 (m,2H, partially obscured), 2.02 (s, 3H), 1.76-1.90 (m, 2H), 1.70-1.37 (m, 2H). LCMS: (M+H+) 430.1, (M+Na+) 452.1.

Example 49: 6-Oxo-2-phenvl-5,6-dihvdro-1H-f1.2Idiazepinof4.5.6-cd]indole-8-carboxvlic acid, potassium sait

To the title compound of Example 39 (3.0 g, 9.39 mmol) was added DMSO (20 mL). To this semi-suspension was added 2N KOH (19 mL, 37.8 mmol). The solution tumed a deep red color andwas stirred for approximately 1.5 hours at room température. The reaction was purified bypréparative HPLC (5-60% CH3CN/H2O) over 60 minutes. Fractions containing the product werelyophilized to afford the title compound (0.8 g) as an orange solid in 25% yield. 1H-NMR (dfe-DMSO): δ 12.21 (s, 1H), 10.12 (s, 1H), 8.16 (d, 1H, J = 1.0 Hz), 8.01 (d, 1H, J = 1.0Hz), 7.73-7.65 (m, 2H), 7.62-7.46 (m, 3H), 7.44 (s, 1H). LCMS: (M+H+) 306.1

Example 50: 3-(2-Methvlphenyl)-/V-(6-oxo-2-phenvl-5.6-dihydro-1 H-f1.21diazepinof4,5.6-cdlindol- 8-vl)propanamide

Préparation of example 50 from the title compound of Example 7 (30 mg, 0.11 mmol), 3-(2-methylphenyl)propanoic acid (27 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,/V’,/V’-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) inΛ/,/V-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gelchromatography (3% methanol in CH2CI2 increasing to 5% methanol in CH2CI2), also in ananalogous manner, followed by methanol trituration afforded the title compound (6 mg, 0.014mmol) as a yellow powder in 13% yield. 1H-NMR (dg-DMSO): δ 12.08 (s, 1H), 10.37 (s, 1H), 10.10 (s, 1H), 8.20 (s, 1H), 7.72-7.42 (m, 7H),7.26-7.05 (m, 4H), 2.96-2.87 (m, 2H), 2.64-2.55 (m, 2H, partially obscured), 2.32 (s, 3H). 01301 106 LCMS: (M+H)‘ 421.1.

Example 51: A/-(6-Oxo-2-phenvl-5,6-dihvdro-1/-/-i1,21diazepinof4,5,6-cGflir)dol-8-vl)-3-(1-tritvl-1/-/- imidazol-4-vl)-propionamide

Préparation of example 51 from the title compound of Example 7 (hydrochloride) {31 mg, 0.10mmol), 3-(1-Trityl-1H-imidazoM-yl)-propionic acid (46 mg, 0.12 mmol), triethyiamine (0.021 mL,0.15 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/\/’,/\/-tetramethyluronium hexafluorophosphate(46 mg, 0.12 mmol) in CH2CI2 (0.4 mL) and W,/V-dimethylformamide (0.4 mL) was carried outanalogously to Example 11. Silica gel chromatography (3% triethyiamine in 5:4:1hexane:CH2CI2:methanol), also in an analogous manner, afforded the title compound (40 mg,0.062 mmol) as a yellow powder in 62% yield. 1H NMR (CDCIsMrmethanol): 5 8.21 (s, 1H), 7.65-7.25 (m, 15H, partially obscurred), 7-10-7.02(m, 8H), 6.65 (s, 1H), 2.99-2.89 (m, 2H), 2.71-2.62 (m, 2H). LCMS: (M+H+) 641.2.

Example 52: 3-(1H-lmidazol-4-vlHV-(6-oxo-2-phenyl-5,6-dihvdro-1/-/-H.21diazepinoi4,5,6-cdlindol- 8-vl)-propionamide: compound with trifluoro-acetic acid

Préparation of example 52 from the title compound of Example 51 (32 mg, 0.050 mmol) and 45%TFA in CH2CI2 (1 mL) was carried out analogously to Example 20. (Deprotection of trityl groupwas effected using the same conditions as for ferf-butoxycarbonyl deprotection.) Isolation, also inan analogous manner, additionally included recrystallization from methanol/ethyl acetate anddiethyl etherto afford the title compound (16 mg, 0.031 mmol) as a yellow powder in 62% yield. 1H NMR (d6-DMSO): 13.95 (br s, 1H), 12.10 (s, 1H), 10.40 (s, 1H), 10.20 (s, 1H), 8.83 (s, 1H),8.13 (s, 1H), 7.70-7.63 (m, 3H), 7.62-7.47 (m, 5H), 7.38 (s, 1H), 3.02 -2.93 (m, 2H), 2.78-2.70 (m,2H). LCMS: (M+H+) 399.2. 013017

Example 53: f(S)-1-(6-Oxo-2-phenvl-5.6-dihvdro-1 /7-f1.2ldiazepinof4.5,6-ccf1indol-8-vlcarbamovl')- 3-phenvl-propvn-carbamic acid fetf-butyl ester 107

10 15

Préparation of example 53 from the title compound of Example 7 (hydrochloride) (31 mg, 0.10mmol), (S)-2-ferf-Butoxycarbonylamino-4-phenyl-butyric acid (34 mg, 0.12 mmol), triethylamine(0.021 mL, 0.15 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,W,/\/’A/-tetramethyluroniumhexafluorophosphate (46 mg, 0.12 mmol) in CH2CI2 (0.4 mL) and /V,/V-dimethylformamide (0.4mL) was carried out analogously to Exemple 11 Silica gel chromatography, (5:4:1hexane:CH2Cl2:methanol), also in an analogous manner, afforded the title compound (40 mg,0.074 mmol) as a yellow powder in 74% yield. 1H NMR (de-DMSO): 12.11 (s, 1H), 10.40 (s, 1H), 10.17 (s, 1H), 8.40 (br s, 1 H), 8.16 (s, 1H), 7.71-7.45 (m, 6H), 7.35-7.15 (m, 6H), 4.06 (m, 1H), 2.77-2.53 (m, 2H, partially obscured), 1.92(m, 2H), 1.42 (s, 9 H). LCMS: (M+H*) 538.1, (M+Na+) 560.2, (M-H)’ 536.0.

Example 54: (2S)-2-Amino-A/-(6-oxo-2-phenvl-5.6-dihvdro-1B-f1.21diazepinof4.5,6-cdlindol-8-vl)-4- phenvl-butyramide: compound with trifluoro-acetic acid

Préparation of example 54 from the title compound of Example 53 (30 mg, 0.056 mmol) and 45%TFA in CH2CI2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogousmanner, afforded the title compound (26 mg, 0.047 mmol) as a yellow powder in 84% yield. 1H NMR (d6-DMSO): δ 12.22 (s, 1H), 10.71 (s, 1H), 10.47 (s, 1H), 8.38 (br s, 3H), 8.13 (s, 1H), 7.72-7.66 (m, 2H), 7.64-7.49 (m, 4H), 7.36-7.28 (m, 2H), 7.27-7.19 (m, 4H), 4.05 (br s, 1H), 2.77-2.65 (m, 2H), 2.21-2.09 (m, 2H). LCMS: (M+H+) 438.2, (M+Na+) 460.1, (M-H)’436.1. 20 013017

Example 55: /V-Methvl-6-oxo-2-phenvl-5.6-dihvdro-1 H-11.21diazepinol4.5.6-cc/1indole-8- carboxamide 108

To a solution of the title compound of Example 49 (0.058 g, 0.17 mmol) in DMSO (4 mL) wasadded triethylamine (0.069 mL, 0.5 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/\/’,/V-tetramethyluronium hexafluorophosphate (0.084 g, 0.22 mmol). After approximately 5 min, 2.0 Mmethylamine in tetrahydrofuran (0.5 mL, 0.25 mmol) was added and the solution was stirred for 2hours. The mixture was purified using préparative HPLC (20-100% CH3CN/H2O containing 0.1%HOAc). The pure fractions were combined and lyophilized to afford the title compound (0.0036 g)in 6.7% yield. 1H-NMR (d6-DMSO): δ 12.46 (s, 1H), 10.45 (s, 1H), 8.58 (s, 1H), 8.20-7.90(m, 2H), 7.85-7.35 (m,6H), 2.79 (s, 3H). LCMS: (M+H+) 319.1.

Example 56: Λ/-Γ2-( 1 H-l midazol-4-vl)ethvn-6-oxo-2-phenvl-5,6-dihvdro-1 H-\ 1.21diazepinof4.5.6- cdlindole-8-carboxamide

Préparation of example 56 from the title compound of Example 49 (0.0956 g, 0.28 mmol), 2-(1/-/-imidazol-4-yl)ethylamine dihydrochloride (0.0618 g, 0.34 mmol), triethylamine (0.2 mL, 1.4 mmol),and 0-(7-azabenzotriazol-1-yl)-W,/\/,/VJ,/V’-tetramethyluronium hexafluorophosphate (0.129 g, 0.34mmol) in DMSO (6 mL) was carried out analogously to Example 58. Préparative HPLC (10-80%CH3CN/H2O), also in an analogous manner, afforded the title compound (0.0021 g) in 18% yield.1H-NMR (de-DMSO): δ 12.48 (s, 1H), 10.49 (s, 1H), 8.77 (t, 1H, J= 5.7 Hz), 8.08 (s, 1H), 8.01 (s,1H), 7.75-7.66(m, 2H), 7.64-7.54 (m, 5H), 7.51 (s, 1H), 6.85 (s, 1H), 3.55-3.45 (m, 2H), 2.84-2.73(t,2H, J = 7.2 Hz). LCMS: (M+H+) 399.1

Anal. Calcd. for C22H,SN6O2 · 0.60 HCl · 0.75 H20: C, 60.91; H, 4.67; N, 19.37. Found: C, 60.74;H, 4.74; N, 19.48. 013017 109

Example 57: 4-Dimethvlamino-/V-(6-oxo-2-phenvl-5,6-dihydro-1 H-fl,21diazepinof4,5.6-ccflindol-8- vl)-butvramide (hvdrochloric sait)

Préparation of example 57 from the title compound of Example 7 (hydrochloride) (27 mg, 0.086mmol), 4-dimethylamino-butyric acid(hÿdrochloride)(17 mg, 0.104 mmol), triethylamine (0.036 mL,0.258 mmol), and 0-(7-azabenzotriazol-1-yl)-W,W,/V',W'-tetramethyluronium hexafluorophosphate(40 mg, 0.104 mmol) in CH2CI2 (0.3 mL) and A/.W-dimethylformamide (0.3 mL) was carried outanalogously to Example 11. Silica gel chromatography (2% triethylamine in 9:1 CH2CI2:methanol)of the freebase afforded, after acidification with HCl, the title compound (18 mg, 0.042 mmol) as ayellow powder in 49% yield. 1H NMR (de-DMSO): δ 12.10 (s, 1H), 10.39 (s, 1H), 10.21 (s, 1H), 9.60 (br s, 1H, HCl), 8.13 (s,1H), 7.69-7.46 (m, 7H), 3.15-3.04 (m, 2H), 2.80 (s, 6H, with fine splitting), 2.45 (t, 2H, partiallyobscurred), 2.02-1.90 (m, 2H). LCMS: (M+H+) 390.2.

Example 58: 6-Oxo-2-phenvl-/V-(2-pvridin-2-ylethvl)-5,6-dihvdro-1 H-Π .21diazepinof4.5.6-ct/lindole- 8-carboxamide

To a solution of the title compound of Example 49 (0.0548 g, 0.16 mmol) in DMSO (1.8 mL) wasadded triethylamine (0.0268 mL, 0.192 mmol), and 0-(7-azabenzotriazol-1-yl)-W,/V,A/’A/’-tetramethyluronium hexafluorophosphate (0.0669 g, 0.176 mmol). After approximatelÿ 5 min, 2-pyridin-2-ylethylamine (0.0215 g, 0.176 mmol) was added and the solution was allowed to stirovemight. The product was purified using préparative HPLC (5-35% CH3CN/H2O). The purefractions were combined and lyophilized to afford the title compound (0.013 g) as a yellow powderin 20% yield. 1H NMR (d6-DMSO): Ç 10.37 (s, 1H), 8.74 (s, 1H), 8.51 (d, 1H, J= 3.0 Hz), 8.01 (d, 2H, J = 11Hz), 7.49-7.71 (m, 7H), 7.20-7.29 (m, 2H), 3.62 (d, 1H, J = 4.9 Hz), 3.02 (t, 1H, J = 6.4 Hz). LCMS: (M+H) 410.

Example 59: terf-Butyl (1R)-1-cvclohexvl-2-oxo-2-t(6-oxo-2-phenvl-5.6-dihvdro-1H- ri,21diazepinof4,5,6-cd1indol-8-vl)amino1ethylcarbamate 0130 1 7 110

Préparation of exemple 59 from the title compound of Example 7 (70 mg, 0.25 mmol), {2R)-{{tert-butoxycarbonyl)amino](cyciohexyl)ethanoic acid (98 mg, 0.38 mmol), triethylamine (0.139 mL, 1.0mmol), and 0-(7-azabenzotriazol-1-yl)-W,W,/V',W-tetramethyluronium hexafluorophosphate (144mg, 0.38 mmol) in Λ/,/V-dimethylformamide (2.0 mL) was carried out analogously to Example 11except that after 24 hours additional (2R)-[(ferÎ-butoxycarbonyl)amino](cyclohexyl)ethanoic acid(32 mg, 0.13 mmol) and 0-(7-azabenzotriazol-1-yl)-/V,A/,/V’,/V-tetramethyluroniumhexafluorophosphate (48 mg, 0.13 mmol) were added to drive the reaction to completion. Silicagel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethylether trituration afforded the title compound (90 mg, 0.17 mmol) as a yellow powder in 70% yield.1H-NMR (de-DMSO): δ 12.09 (s, 1H), 11.43 (s, 1H), 10.39 (s, 1K), 10.14 (s, Ί H), 8.16 (s, 1H),7.70-7.64 (m, 3H), 7.61-7.54 (m, 2H), 7.53-7.46 (m, 2H), 3.96 (m, 1H), 1.79-1.49 (m, 6H), 1.41-1.29 (m, 14H, contains singlet at 1.38). LCMS: (M+H)‘ 514.2.

Example 60: (2R)-2-Amino-2-cyclohexyl-/V-f6-oxo-2-phenvl-5.6-dihvdro-1 H-[1.21diazepinof4.5.6- cdlindol-8-vl)ethanamidetrifluoroacetate

Préparation of example 60 from the title compound of Example 59 (90 mg, 0.17 mmol), and 1:1TFA/CH2CI2 (5 mL) was carried out analogously to Example 20. Isolation, also in an analogousmanner, included a further trituration with methanol/diethyl ether and afforded the title compound(70 mg, 0.013 mmol) as an orange/yellow powder in 78% yield. 1H-NMR (d6-DMSO): δ 12.22 (s, 1 H), 10.63 (s, 1H), 10.47 (s, 1 H), 8.22 (br s, 2H), 8.14 (s, 1H), 7.72-7.66 (m, 3H), 7.64-7.49 (m, 4H), 3.72 (m, 1 H), 1.91-1.59 (m, 6H), 1.29-1.14 (m, 5H, partiallyobscured by diethyl ether). LCMS: (M+H+) 416.2, (M+Na+) 438.2. 013017 111

Example 61: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid f6-oxo-2-phenyl-5,6-dihvdro-1H- f1,2ldiazepinof4,5,6-cdlindol-8-yl)-amide

HN-N

5 Préparation of example 61 from the title compound of Example 7 (198 mg, 0.72 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (175 mg, 1.08 mmol; as described by A. Thurkauf, et al., J.Med. Chem. 43, 3923-3932, (2000)), triethylamine (0.401 mL, 2.88 mmol), and O-(7-azabenzotriazol-1-yl)-W,W,W’/V’-tetramethyluronium hexafluorophosphate (411 mg, 1.08 mmol) inW,W-dimethylforrnarnide (10.0 mL) was carried out analogously to Example 11. Silica gel 10 chromatography (3% methanol in CH2CI2), also in an analogous manner, followed by collection ona frit and subséquent washing with diethyl ether afforded the title compound (86 mg, 0.20 mmol)as a yellow powder in 28% yield. 1H-NMR (d6-DMSO): 8 12.09 (s, 1H), 10.44 (s, 1H), 10.37 (s, 1H), 8.16 (d, 1H, J = 1.6 Hz), 7.69-7.63 (m, 3H), 7.60-7.46 (m, 4H), 7.34-7.17 (m, 5H), 2.44-2.35 (m, 1H), 2.13-2.05 (m, 1H), 1.55- 15 1.46 (m, 1 H), 1.42-1.34 (m, 1 H). LCMS: (M+H+) 421.1.

Step 1. Préparation of 2-Phenyl-6-[((1R,2R)-2-phenyl-cyclopropanecarbonyl)-amino]-1H-20 indole-4-carboxyIic acid methyl ester61(a)

Préparation from Intermediate 7(a) (3.83 g, 12.64 mmol), (1R,2R)-2-phenyl- cyclopropanecarboxylic acid (2.27 mg, 13.97 mmol), triethylamine (3.52 mL, 25.28 mmol), and O-(7~azabenzotriazol-1-yl)-/V,/V,/V’,/V-tetramethyluronium hexafluorophosphate (5.31g, 13.97 mmol)in CH2CI2 (6.5 mL) and /V,/V-dimethylformamide (6.5 mL) was carried out analogously to Example 013017 112 11. Extractive work-up from ethyl acetate and saturated aqueous NaHCO3 afforded the crudeproduct as an oil in Λ/,/V-dimethylformamide. Diethyl ether (c.a. 500 mL) and CH2CI2 (80 mL) wereadded and the mixture was capped and stirred vigorously ovemight whereupon the oil wasconverted to greenish tan solids which were collected by filtration and washed with diethyl ether,methanol, and water. The filtrate was evaporated to an oil and water was added to precipitate asecond batch of solids which was also collected by filtration and also washed with methanol andwater. Both batches of precipitated and washed solids were combined to give 4.18 g of desiredproduct. In addition, the final fitrate was evaporated and subjected to silica gel chromatographyeluting with 1:1 hexane:acetone to give a small amount of additional product (0.275 mg).Thecombined batches afforded Intermediate 61 (a) (4.46 g, 10.86 mmol) as a tan solid in 86% yield.Step 2. Préparation of 3-formyl-2-phenyl-6-[((1R,2R)-2-phenyl-cyclopropanecarbonyl)-amino]-1 H-in dole-4-carboxy lie acid methyl ester 61 (b)

Intermediate 61 (a) (4.02 g, 9.79 mmol) was dissolved in CH2CI2 (80 mL) and treated withVilsmeier reagent (2.94 mL) in a manner similar to that described in step 4 of Example 3. Afterc.a. 10 min stirring at ice bath température followed by 10 min at room tempeature, the volume ofCH2CI2 was reduced under vacuum, With ice bath cooling and stirring, Na2CO3 (c.a. 1.2 g) in H2O(10 mL) was added as a paste to the reaction. Additional H2O (20 mL) was then added to the stillcool reaction. Methanol (c.a. 100 mL) was added and the reaction was allowed to warm to roomtempérature, still stirring, whereup the slow évolution of gas was observed. After 4 hours, thevolume of the mixture was reduced under vacuum, and CH2CI2 was added to adjust the solventcomposition to approximately 4:1 CH2CI2:methanol. Precipitated Na2CO3 was then removed byfiltration, and the volume of filtrate was reduced under vacuum leaving mostly methanol as thesolvent. Ethyl acetate was added and mixture was then dried (Na2SO4) and filtered andevaporated to give yellow solids. Silica gel chromatography (eluting with 4:1 hexane:acetoneincreasing to 1:1 hexane:acetone) afforded Intermediate 61 (b) (4.2 g, 9.64 mmol) as a yellowpowder in c.a. 98% yield.

Step 3. Préparation of Title Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide

Intermediate 61 (b) (4.1 g, 9.41 mmol) acetic acid (0.78 mL, 13.63 mmol) and H2NNH2 ' H2O (1.37mL, 28.23 mmol) in anhydrous methanol (100 mL) were refluxed in manner similar to thatdescribed for Example 3, step 5. The resulting precipitate was collected by filtration and washedwith a minimum amount of methanol affording the title compound (3.5 g, 8.28 mmol) as a yellowpowder in 88% yield. 013017

Example 62: (1S,2S)-2-Phenvl-cvciopropanecarboxylic acid i6-oxo-2-phenvl-5.6-dihvdro-1/-/- f1.2|diazepino[4.5,6-ccflindol-8-yl)-amide 113

HN-N 5 Préparation of example 62 from the title compound of Example 7 (79 mg, 0.28 mmol), (1S,2S)-2-phenylcyclopropanecarboxyiic acid (60 mg, 0.37 mmol; as described by A. Thurkauf, et al., J.Med. Chem. 43, 3923-3932, (2000)), triethylamine (0.160 mL, 1.14 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/\/,/V’,A/-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) inW,W-dimethylformamide (10.0 mL) was carried out analogously to Example 11. Silica gel 10 chromatography (5% methanol in CH2CI2), also in an analogous manner, followed by triturationwith methanol afforded the title compound (26 mg, 0.06 mmol) as a yellow powder in 22% yield.1H-NMR (de-DMSO): δ 12.10 (s, 1H), 10.44 (s, 1H), 10.37 (s, 1 H), 8.17 (s, 1H), 7.72-7.43 (m, 7H),7.35-7.26 (m, 2H), 7.24-7.17 (m, 3H), 2.40 (m, 1H), 2.10 (m, 1 H), 1.52 (m, 1H), 1.38 (m, 1H).LCMS: (M+H+) 421.3, (M+Na+) 423.2. 15 Example 63: 6-Oxo-2-phenvl-A/-f2-(1 /-/-tetraazol-5-vl)ethvÎ1-5.6-dihvdro-1 H-H .21diazepinol4.5.6- ccflindole-8-carboxamide

HN—N

Préparation of example 63 from the title compound of Example 49 (0.0989 g, 0.288 mmol), 2-(177-tetraazol-5-yl)ethylamine (0.072 g, 0.317 mmol), triethylamine (0.0883 mL, 0.634 mmol), and O- 20 (7-azabenzotriazol-1-yl)-/V,A/,W',A/-tetrarnethyliironium hexafluorophosphate (0.121 g, 0.317mmol) in DMSO (2 mL) was carried out analogously to Example 58. Préparative HPLC (25-80%CH3CN/H2O), also in an analogous manner, afforded the title compound (0.002 g) in 1.7% yield. 1H NMR (d6-DMSO): δ 12.50 (s, 1H), 10.49 (s, 1H), 8.83 (t, 1H, J = 4.9 Hz), 8.05 (s, 1H), 7.98 (s,1H), 7.70 (d, 2H, J = 7.6 Hz), 7.51-7.62 (m, 4H), 3.64 (q, 2H, J = 6.1 Hz), 3.14 (t, 2H, J = 6.8 Hz). 25 HRMS caiculated for C20H17N8O2 401.1474 (M+H), found 401.1476. 013017

Example 64: /V-r2-(4-Morpholinyl)ethvn-6-oxo-2-phenvl-5.6-dihvdro-1 H-l 1.21diazepinor4.5,6- cdlindole-8-carboxamide 114

10

Préparation of example 64 from the tîtle compound of Example 49 (0.0991 g, 0.289 mmol), 2-morpholin-4-ylethylamine (0.041 g, 0.317 mmol), triethylamine (0.0483 mL, 0.347 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,/V',/V-tetramethyluronium hexafluorophosphate (0.121 g, 0.317mmol) in DMSO (2 mL) was carried out analogously to Example 58. Préparative HPLC (10-80%CH3CN/H2O), also in an analogous manner, afforded the title compound (0.018 g) in 15% yield. ’H NMR (d6-DMSO): δ 12.48 (s, 1 H), 10.49 (s, 1H), 8.62 (t, 1H, J = 5.3 Hz), 8.07 (s, 1H), 8.00 (s,1H), 7.70 (d, 2H, J = 6.8 Hz), 7.51-7.62 (m, 4H), 3.57 (t, 4H, J = 4.3 Hz), 3.37-3.43 (m, 2H), 2.41(brs, 6H). HRMS calculated for C23H24N5O3 418.1879 (M+H), found 418.1858.

Example_65:_6-Oxo-/V-f3-(2-oxo-1-pvrrolidinyQpropvn-2-phenyl-5.6-dihydro-1/-/- f1.2ldiazepinof4.5,6-cdlindole-8-carboxamide

Préparation of example 65 from the title compound of Example 49 (0.109 g, 0.319 mmol), 1-(3-aminopropyl)pyrrolidin-2-one (0.05 g, 0.351 mmol), triethylamine (0.0534 mL, 0.383 mmol), andO-(7-azabenzotriazol-1-yl)-W,A/,/V',W-tetramethyluronium hexafluorophosphate (0.133 g, 0.351mmol) in DMSO (2 mL) was carried out analogously to Example 58. Préparative HPLC (10-80% 20 CH3CN/H2O), also in an analogous manner, afforded the title compound (0.035 g) in 26% yield. 1H NMR (d6-DMSO): δ 12.54 (s, 1H), 10.51 (s, 1H), 8.66 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1 H), 7.70(d, 2H, J = 7.2 Hz), 7.53-7.62 (m, 4H), 3.23-3.37 (m' 6H), 2.21 (t, 2H, J = 7.9 Hz), 1.89-1.96 (m,2H), 1.72 (t, 2H, J = 6.8 Hz). HRMS calculated for C24H24N5O3 430.1879 (M+H), found 430.1899. 013017

Example 66: 2-Ethvlsulfanyl-A/-(6-oxo-2-phenvl-5,6-dihvdro-1/-/-n.21diazepinof4.5.6-ccnindol-8- vl)-nicotinamide 115

Préparation of example 66 from the title compound of Example 7 (hydrochloride) (30 mg, 0.0965 mmol), 2-ethylsulfanyl-nicotinic acid (22 mg, 0.12 mmol), triethylamine (0.020 mL, 0.14 mmol),and O-(7-azabenzotriazol-1-yl)-/V,/V,A/’,W-tetramethyluronium hexafluorophosphate (46 mg, 0.12mmol) in CH2CI2 (0.4 mL) and W,/V-dimethylformamide (0.4 mL) was carried out analogously to

Example 11. Silica gel chromatography (pre-rinsed silica with 3% triethylamine in ethyl acetate,eluted with 3% triethylamine in 19:6:1 ethyl acetate:hexane:methanol), also in an analogous 10 manner, afforded the title compound (7 mg, 0.016 mmol) as a yellow powder in 17% yield. 1H NMR (d6-DMSO): § 12.15 (s, ÏH), 10.60 (s, 1H), 10.39 (s, 1H), 8.59 (s, 1H, with fine splitting),8.22 (s, 1H), 7.95 (m,1H), 7.82 (s, 1H), 7.72-7.48 (m, 6H), 7.25 (m,1H), 3.21-3.10 (m, 2H, partiallyobscured), 1.35-1.23 (m, 3H). LCMS: (M+H+) 442.3, (M+Na+) 464.1. 15 Example 67: (1 R.2R)-2-Phenvl-cvclopropanecarboxvlic acid (6-oxo-5,6-dihvdro-1 Η-Γ 1.21diazepinof4.5,6- ccflindol-8-vl)-amide: and f 1 S.2S)-2-Phenvl-cvclopropanecarboxylic acid (6-oxo-5,6-dihvdro-1 H-ï 1.21diazepinor4.5,6- cdlindol-8-vl)-amide 20

Préparation of example 67 from the title compound of Example 2 (freebase) (21 mg, 0.105 mmol),+ trans-2-phenyl-1-cyclopropanecarboxylic acid (20 mg, 0.126 mmol), triethylamine (0.044 mL,0.315 mmol), and 0-(7-azabenzotriazol-1-yl)-A/,/V,/v;/V’-tetramethyluroniurn hexafluorophosphate 25 (48 mg, 0.126 mmol) in CH2CI2 (0.3 mL) and /V,/V-dimethylformamide (0.3 mL) was carried put analogously to Example 11. Silica gel chromatography (5:4:1 hexane:CH2CI2:methanol foliowedby 9:1 CH2CI2:methanoi), also in an analogous manner, afforded the title compound (20 mg, 0.058mmol) (mixture of trans diastereomers) as a yellow powder in 55% yield. 013017 ’H NMR (d6-DMSO): δ. 11.72 (s, 1H), 10.38 (s, 1H), 10.25 (s, 1H), 8.13 (s, 1H), 7.56 {s, 1H, overlapping), 7.55 (s, 1H, overlapping), 7.46 (s, 1H), 7.37-7.13 (m, 5H), 2.39 (m, 1H), 2.10 (m, 1H), 1.51 (m, 1H), 1.39 (m, 1H). LCMS: (M+H+) 345.4, (M+Na+) 367.3. 5 Example 68: 8-(3-Chloro-benzvlamino)-2-phenvl-1,5-dihydro-ri ,2ldiazepinoi4.5,6-cdlindol-6-one

HN-N 116

To the title compound of Example 7 (hydrochloride) (40 mg, 0.13 mmol), and triethylamine (0.053ml_, 0.38 mmol) in A/./V-dimethylformamide (0.9 mL) was added 1-bromomethyl-3-chloro-benzene(0.17 mL, 0.13 mmol) dropwise with stirring. After stirring overnight, the mixture was 10 chromatographed on silica eluting with 2:1 hexane:ethyl acetate to afford, after isolation, the titlecompound (36 mg, 0.090 mmol) as a yellow powder in 71% yield. 1H NMR (ds-DMSO): δ 11.59 (s, 1H, exchanges), 10.22 (s, 1H, exchanges), 7.60-7.27 (m, 10H),7.08 (s, 1H), 6.60 (t, 1H, J = 4.9 Hz, exchanges), 6.45 (s, 1H), 4.36 (m, 2H). LCMS: (M+H+) 401.3,403.3. 15 Anal. Calcd. for C23H17N4OCI ’ 0.3 H2O: C, 67.99; H, 4.37; N, 13.79.

Found: C, 67.98; H, 4.35; N, 13.58.

Example 69: 8-fBis-(3-chloro-benzvl)-amino1-2-phenvl-1,5-dihvdro-f1,21diazepinol4.5.6-cdlindol-6- one

20 The title compound (7 mg, 0.013 mmol) was isolated as a yellow powder in 10% yield as a by-product from the synthesis outlined in Example 68. 1H NMR (d4-rnethanol): δ 7.51-7.31 (m, 6H), 7.25-7.10 (m, 9H), 6.64 (s, 1H), 4.64 (s, 4H). LCMS: (M+H+) 525.3. 013017

Example 70: A/-r2-(Dimethvlamino)ethvl1-6-oxo-2-phenyl-5,6-dihvdro-1 W1,2ldiazepinof4,5.6- cdlindole-8-carboxamide trifluoroacetate 117

10 15 20

Préparation of example 70 from the title compound of Example 49 (0.08 g, 0.23 mmol), N,N-dimethylethane-1,2-diamine (0.0247 g, 0.28 mmol), triethylamine (0.17 mL, 1.2 mmol), and O-(7-azabenzotriazol-1-yl)-/\/,/V,A/',/V-tetramethyluronium hexafluorophosphate (0.106 g, 0.28 mmol) inDMSO (6 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid) also in an analogous manner afforded the titlecompound (0.0076 g) in 6.8% yield. 1H NMR (de-DMSO): δ 12.53 (s, 1H), 10.54 (s, 1H), 9.30 (s, 1 H), 8.84 (t, 1H, J = 5.5 Hz), 8.12 (s,1H), 8.04 (s, 1H), 7.75-7.67(m, 2H), 7.66-7.53 (m, 3H), 7.52 (s, 1H), 3.62 (m, 2H), 3.39 (m, 2H),2.86 (s, 6H). LCMS: (M+H+) 376.1 HRMS: C21H21N5O2 · H: 376.1774. Found: 376.1785.

Example 71a: (S)-2-Dimethvlamino-A/-f6-oxo-2-phenvl-5,6-dihydro-1 /741,2idiazepino[4,5,6- ccflindol-8-vl)-3-phenvl-propionamide fhvdrochloric sait)

Préparation from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (S)-2-Dimethylamino-3-phenyl-propionic acid (30 mg, 0.154 mmol), triethylamine (0.071 mL, 0.512mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V’-tetramethyluronium hexafluorophosphate (59mg, 0.154 mmol) in CH2CI2 (0.4 mL) and W,W-dimethylformamide (0.4 mL) was carried outanalogously to Example 11. Siiica gel chromatography (elute with 1.5% triethylamine in CH2CI2followed by 1.5% triethylamine in 9:1 CH2CI2:methanol), also in an analogous manner, affordedthe freebase of the title compound (46 mg, 0.10 mmol) in three separate batches for a combined80% yield. Two of the batches were carried on to Examples 71b and 71c respectively. To the thirdbatch (8 mg, 0.018 mmol) was added tetrahydrofuran and 1.2 équivalents of HCl in dioxane (froma 4M stock solution). After évaporation, trituration with diethyl ether and 1:1 CH2CI2:hexane gavethe titie compound (6 mg, 0.012 mmol) as a yellow powder in 67% yield for the sait formation. 25 1Η NMR (d6-DMSO): δ. 12.25 (s, 1Η, exchanges), 10.76 (br s, 2H, exchanges), 10.42 (s, 1H, exchanges), 7.95 (s, 1 H), 7.72-7.45 (m, 7H), 7.35-7.16 (m,5H), 4.28 (m, 1 H), 3.05 -2.90 (m, 6H). LCMS (freebase): (M+H+) 452.3, (M+Na+) 474.3.

Example 71b: (S)-2-Dimethvlamino-/V-f6-oxo-2-phenvl-5,6-dihvdro-1W1,21diazepinof4.5,6- 5 cdlindol-8-vl)-3-phenvl-propionamide 118

HN—N

One batch of freebase (S)-2-Dimethylamino-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1,2]diazepino[4,5,6-cd|indol-8-yl)-3-phenyl-propionamide (13 mg, 0.029 mmoi) from Example 71awas triturated with 1:1 diethyl ether:hexane to give the purîfied title compound (12 mg, 0.027 10 mmol) as a yellow powder in 93% yield for the trituration.

Example 71c: (S)-2-Dimethvlamino-<V-(6-oxo-2-phenvl-5,6-dihvdro-1H-n.21diazepinof4.5,6- cdlindol-8-vn-3-phenyl-propionamide: compound with (2R,3R)-2,3-dihvdroxy-succinic acid HO·

One batch of freebase (S)-2-Dimethylamino-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- 15 [1,2ldiazepino{4,5,6-cd]indol-8-yl)-3-phenyl-propionamide (22 mg, 0.049 mmol) from Example 71awas triturated with 1:1 diethyl ether:hexane giving purîfied material (20 mg, 0.044 mmol). A portion(10 mg, 0.022 mmol) was then dissolved in a small amount of c.a. 1:1 tetrahydrofurammethanoland treated with L-tartaric acid (3.3 mg, 0.022 mmol). The volatile components of the resultingclear solution were removed under a stream of argon. To the resulting yellow oil was added 20 diethyl ether plus one drop of methanol giving a fine yellow precipitate which was isolated bydecanting most of the liquid and subséquent high vacuum romoval of the remaining volatilecomponents to afford the title compound as a tartrate sait (13 mg, 0.022 mmol) in quantitativeyield. 119

Example 72: Ν-(244-ί^6^ν^ίπο)Γη6{|·ινΙ1ρί)6ηνΙ}-6-οχο-5,6-όιίινΰΓθ-1Η-ί1,21όί326Ρίηοί4,5.6- crflindol-8-vl)acetamide trifluoroacetate

Intermediate 73(c)of Example 73 1. (CH3SO2)2O2,4,6-Collidine, CK2CI2 2. CH3NH2 3. Boc2O, EtgN, CH2CI2 64%

1. POCI3. DMF, CH2CI2

2. NH2NH2.H2O, AcOH -:->.

MeOH, reflux 3. TFA, CH2CI2,4%

HN-N

TFA

Step 1. Préparation of Methyl 6-(acetylamino)-2-(3-{[{[(l,1-dimethylethyl)oxy]carbonyl}(methyl)amino] methyl)phenyl)-1 H-indole-4-carboxylate 72(a)With stirring, to Intermediate 73(c) of Example 73 (54 mg, 0.16 mmol) in CH2CI2 (2.5 mL) is added2,4,6-trimethylpyridine (0.11 mL, 0.80 mmol) followed by methanesulfonic anhydride (42 mg, 0.23mmol). After 3.5 hours, additional methanesulfonic anhydride (7 mg, 0.04 mmol) is added, and themixture is stirred for an additional 1 hour whereupon methylamine in tetrahydrofuran (2.0 mL, 2.0M) is added, and the reaction is stirred overnight at room température. Following évaporation ofthe volatile components, CH2CI2 (2.0 mL), triethylamine (0.064 mL, 0.46 mmol), and di-terf-butyldicarbonate (50 mg, 0.23 mmol) are added and the reaction is stirred for 2.5 hours whereupon,after removal of the volatile components, the crude product was purified by silica gelchromatography eluting with 1:1 ethyl acetaterhexane to afford Intermediate 72(a) (46 mg, 0.10mmol) in 64% yield.

Step 2. Préparation of Title Compound: /V-(2-(4-[(Methylamino)methyl]phenyl}-6-oxo-5,6-dîhydro-1 H-[1,2]diazepino[4,5,6-cd]indo!-8-yI)acetamide trifluoroacetate

In a manner similar to that described for Example 3, step 4, Intermediate 72(a) (45 mg, 0.10mmole), in CH2CI2 (1.5 mL) was treated with a premixed Vilsmeiêr reagent consisting of POCI3(0.021 mL, 0.23 mmol) and tyN-dimethylformamide (0.05 mL, 0.65 mmol). After 2 h, 2 N sodiumacetate in water was added, and the crude 3-formylated product was isolated by extractive workup using ethyl acetate. After évaporation of the volatile components, methanol (1.5 mL), H2NNH2.H2O (0.015 mL, 0.31 mmol) and acetic acid (0.010 mL, 0.17 mmol) were added, and the mixturewas heated in a 70 °C oil bath for 45 min. Purification was effected using silica gelchromatography eluting with 3:2 ethyl acetate:hexane. The protected intermediate, 1,1-dimethylethyl {4-[8-(acetylamino)-6-oxo-5,6-dihydro-1H-[1,2]diazepino{4,5,6-cc(|indol-2- 013017 120 yljphenyl}methyl(methyl)carbamate, was treated with 1:1 TFA/CH2CI2 (5 mL) analogously toExample 20. Isolation afforded the title compound (2 mg, 0.004 mmol) in 4% yield. LCMS: (M+H+) 362.3.

Example 73: /V-f2-(3-Dimethvlaminomethvl-phenvl)-6-oxo-5,6-dihvdro-1 Η-Γ1,2ldiazepinof4.5.6- cdlindol-8-vn-2-fluoro-3-trifluoromethvl-benzamide

Intermediate 6(b),Example 6

OAc (C6H5CN)2PdCI2, Culf-Bu3P, DIPEA,Dioxane, 70 °C, 87%

73(b) •OAc H2SO4, 0 °C, 52%

1. (CH3SO2)2O2,4,6-Collidine, CH2CI2

2. (CH3)2NH :->-

3. 4N HCl (Dioxane). MeOH, 90 °C 4. POCI3. DMF, CH2CI2 5. NH2NH2.H2O,AcOHMeOH, reflux, 30%

10 Step 1. Préparation of 2-(3-Acetoxymethyl-phenylethynyl)-3,5-bis-acetylamino-benzoic acidmethyl ester 73(b) A mixture of (C6H5CN)2PdCI2 (0.8 g, 2 mmol). Cul (0.267 g. 1.4 mmol), and tri-ferf-butyl-phosphane (1.05 mL, 4 mmol) in dioxane (35 mL, 2.0 M) was stirred at 22 °C for 0.25 hours.Diisopropyiamine (17.1 mL, 122 mmol), Intermediate 6(b) of Example 6 (23 g, 69.9 mmol), acetic 15 acid 3-ethynyl-benzyl ester (17 g, 98.0 mmol) (see beiow for préparation) and N,N-dimethylformamide (35 mL, 2.0 M) were added sequentially. The reaction mixture stirred at 70 °Cfor 16 hours. Ethyl acetate (300 mL) was added and the salts were filtered through diatomaceous 013017 121 earth. The solvent was removed under reduced pressure, and the resulting solid was trituratedwith ethyl acetate (25 mL), diçhloromethane (50 mL) and diethyl ether (25 mL). The precipitatewas collected by filtration and Washed with 5% diçhloromethane in diethyl ether (100 mL) toafford, after drying, Intermediate 73(b) (25.7 g) in 87% yield as a white powder. ’H-NMR (de-DMSO): δ 10.35 (s, 1 H), 9.54 (s, 1H), 8.21 (d, 1 H, J = 2.1 Hz), 8.08 (d, 1H, J = 2.1Hz), 7.58-7.38 (m, 4H), 5.12 (s, 2H), 3.90 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H). LCMS: (M-H*) 421.3

For step 1, compound 73(a) (acetic acid 3-ethynyl-benzyl ester) was prepared as follows:

Step 1a - 1c.

1. KF, MeOH, (t->

2. NaBH4, MeOH, O °C

.OH 73{a2)

>Ac 73ia)

(CH3CO2)2O, DIPEA 4-DMAP, CH2CI2, 63%

Step 1a: Préparation of crude 3-trimethvlsilanvlethynvl-benzaldehvde 73(a113-Bromobenzaldehyde (30 g, 162 mmol), ethynyl-trimethyl-silane (30 mL, 211 mmol),triphenylphosphine (2.13 g, 8 mmol), palladium (II) acetate (0.91 g, 4 mmol) and triethylamine(540 mL, 0.3 M) were heated at 90 °C for 5 hourê, after cooling to ambient température, the 15 mixture was filtered. The filtrate was evaporated, and the residue was subjected to silica gelchromatography (hexane to 4:96 diethyl ether/hexane) to afford 3-trimethylsilanylethynyl- . benzaldehyde 73(a1).

Step 1b: Préparation of crude (3-ethvnvl-phenvh-methanol 73(a2)

To 3-trimethylsilanylethynyl-benzaldehyde 73(a1) from step 1a in methanol (540 mL, 0.3 M) was20 added KF (18.8 g, 324 mmol), and the resulting mixture stirred at 22 °C for 6 hours. After coolingto 0 °C, NaBH4 (6.13 g, 162 mmol) was carefully added over 0.5 hours. Aqueous saturated NH4CIwas carefully added and the volatiles were removed in vacuo. Ethyl acetate (200 mL) was added,and the organic phase was washed with water and a saturated aqueous NaCI solution, dried over

MgSO4 and filtered. The volatiles were removed in vacuo to afford crude (3-ethynyl-phenyl)-25 methanol 73(a2).

Step 1c: Préparation of acetic acid 3-ethvnvl-benzvl 73(a)

Crude (3-ethynyl-phenyl)-methanol 73(a2) from step 1b, acetic anhydride (20 mL, 21 mmol),diisopropylethylamine (85 mL, 486 mmol) and 4-dimethylamino-pyridine (0.3963.2 mmol) were ο 13017 122 stirred in CH2CI2 (540 mL, 0.3 M) for 0.5 hours. Aqueous saturated NH4CI (100 mL) was carefullyadded and the organic phase washed with brine, dried over MgSO4 and filtered. The volatileswere removed in vacuo to afford, after silica gel chromatography (hexanes to 12:88 diethylether/hexanes), acetic acid 3-ethynyl-benzyl (a) (17.83 g) in 63% yield. 5 1H-NMR (d6-DMSO): 57.32-7.01 (m, 4H), 4.85 (s, 2H), 4.01 (s, 1H), 1.89 (s, 3H).

Step 2. Préparation of 6-Acetylamïno-2-(3-hydroxymethyl-phenyl)-1H-indole-4-carboxylicacid methyl ester 73(c)

In a manner analogous to Step 4 of Example 6, Intermediate 73(b) (24 g, 56.8 mmol) was cyclizedto Intermediate 73(c) (10.1 g) in 52% yield. 10 1H-NMR (d6-DMSO): δ 11.89 (s, 1H), 10.16 (s, 1H), 8.35 (s, 1H), 7.89 (bs, 2H), 7.51 (d, 1 H, J =7.9 Hz), 7.49 (dd, 1H, J = 7.7, 7.5 Hz), 7.33 (bs, 2H), 5.37 (dd, 1H, J = 5.8, 5.7 Hz), 4.64 (d, 2H, J= 5.65 Hz), 3.99 (s, 3H), 2.13 (s, 3H). LCMS: (M+H+) 339.0

Step 3. Préparation of 8-Amino-2-(3-dimethylaminomethyl-phenyl)-1,5-dihydro- 15 [1,2]diazepino [4,5,6-cd]indol-6-one 73(d)

To a solution of Intermediate 73(c) (1 g, 3 mmol) in dichloromethane (0.1 M, 30 mL) was added2,4,6-Collidine (1.56 mL, 12 mmol) followed by (CH3SO2)2O (0.62 g, 3.6 mmoL). After stirring for 2hours, dimethylamine (5.6 M solution in éthanol, 2.6 mL, 15 mmol) was added and the reactionmixture stirred for 24 hours at 22 °C. The volatiles were removed In vacuo, and the crude mixture 20 was dissolved in methanol (15 mL). Anhydrous 4M HCl in dioxane (15 mL, 60 mmol) was carefullyadded, and the solution heated at 90 °C for 2.5 hours. After cooling at 22 °C, the volatiles wereremoved in vacuo and the crude 6-amino-2-(3-dimethylaminomethyl-phenyl)-1H-indole-4-carboxylic acid methyl ester was formylated and cyclized in a manner analogous to steps 4 and 5of Example 3. Silica gel chromatography (90:10 to 75:25 CH2CI2/ 2M ammonia in isopropyl 25 alcohol) provided Intermediate 73(d) (0.3 g, 0.9 mmol) in 30% yield. 1H-NMR (d6-DMSO): δ 11.54 (s, 1H), 10.15 (s, 1H), 7.55-7.32 (m, 5H), 6.98 (d, 1H, J= 1.3 Hz),6.65 (d, 1H, J = 1.4 Hz), 5.2 (bs, 2H), 3.49 (b, 2H), 2.20 (bs, 6H). LCMS: (M+H+) 334.2

Step 4. Préparation of Title Compound: Af-[2-(3-Dimethylaminomethyl-phenyi)-6-oxo-5,6- 30 dihydro-1H-[1,2]diazepino[4,5,6-cd]indoI-8-yl]-2-fluoro-3-trifluoromethyl-benzamide

Préparation from Intermediate 73(d) (0.11 g, 0.4 mmol), 2-Fiuoro-3-trifluoromethyl-benzoic acid (0.103 g, 0.6 mmol), triethylamine (0.183 mL, 1.6 mmol), O-(7-azabenzotriazol-1-yl)-A/,/V,/V’,/V- tetramethyluronium hexafluorophosphate (0.188 g, 0.6 mmol) and Λ/,/V-dimethylformamide (0.2 M, 1.7 mL) was carried out analogously to Example 11. Silica gel chromatography (90:10 to 80:20 013017 123 CH2CI2/ 2M ammonia in isopropyl alcohol) afforded the title compound (0.11 g) as a yellowpowder in 64% yield. 1H-NMR (de-DMSO): δ 12.26 (s, 1 H), 10.84 (s, 1 H), 10.51 (s, 1H), 9.62 (b, 1H), 8.29 (d, 1 H, J =1.4 Hz), 8.08-7.94 (m, 2H), 7.85-7.53 (m, 7H), 4.39 (s, 2H), 2.73 (s, 6H). 5 LCMS: (M+H+) 524.2.

Example_74:_Methvl_1-f3-(methvlamino)propvl1-6-oxo-2-phenvl-5.6-dihvdro-1H- Γ1.2idiazepinof4.5.6-cd]indole-8-carboxvlate trifluoroacetate

To a solution of the title compound from Example 39 (0.32 g, 1 mmol) in anhydrous DMSO (1010 mL) was added NaH (60% suspension in minerai oil) (0.088 g, 2.2 mmol). The mixture wasallowed to stir for 5 min whereupon 1,2-dibromopropane (0.24 g, 1.2 mmol) was added. Themixture was allowed to stir overnight at room température at which point a 2M solution ofmethylamine in methanol (4 mL, 8 mmol) was added. The mixture was subjected to préparative HPLC (20-50% CH3CN/H2O containing 0.1% trifluoroacetic acid). The purest fractions were15 combined and lyophilized to afford the title compound (0.0209 g) in 4.1% yield. 1H NMR (de-DMSO): δ 10.61 (s, 1H), 8.39 (d, 1H, J = 1.0 Hz), 8.22 (d, 1H, J = 1.0 Hz), 7.70-7.55(m, 5H), 7.07 (s, 1H), 4.41 (t, 2H, J = 7.2 Hz), 3.92 (s, 3H), 2.80-2.60 (broad, 2H), 2.43 (s,3H), 1.95-1.75 (m,2H). LCMS: (M+H+) 391.2 20 HRMS: C22H22N4O3· H: 391.1770. Found: 391.1768.

Example_75:_6-Oxo-2-phenyl-/V-((1,2-fr~ans)-2-phenvlcvclopropvl)-5,6-dihvdro-1H- f1,21diazepinof4.5.6-ccfltndole-8-carboxamide

Préparation of example 75 from the title compound of Example 49 (0.34 g, 1 mmol), +(1,2-frans)-25 2-phenylcyclopropylamine hydrochloride (0.2 g, 1.2 mmol), triethylamine (0.28 mL, 2 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (0.46 g, 1.2 mmol) 013017 124 in DMSO (10 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0145 g) in 3.5% yield. 1H NMR (de-DMSO): δ 12.46 (s, 1 H), 10.47 (s, 1 H), 8.88 (d, 1H, J = 4.4 Hz), 8.10 (d, 1H, J = 1.4Hz), 8.02 (d, 1H, J = 1.4 Hz), 7.75-7.66(m, 2H), 7.64-7.53 (m, 3H), 7.51 (s, 1H), 7.32-7.25 (m,2H), 7.23-7.10 (m, 3H), 3.08 (m, 1H), 2.11 (m, 1H), 1.41 (m, 1H), 1.23 (m, 1H). LCMS: (M+H+) 421.1.

Example 76: A/-(2-Hvdroxv-2-phenvlethvl)-6-oxo-2-phenvl-5.6-dihvdro-1/7-|1,21diazepinor4,5,6- cdlindole-8-carboxamide

To a solution of the title compound of Example 49 (0.105 g, 0.306 mmol) in DMSO (2 mL) wasadded triethylamine (0.085 mL, 0.612 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/V,/V',/V-tetramethyluronium hexafluorophosphate (0.232 g, 0.612 mmol). After approximately 5 min, 2-amino-1-phenylethanol (0.084 g, 0.612 mmol) was added, and the mixture was stirred overnight.The mixture was subjected to préparative HPLC (20-100% CH3CN/H2O containing 0.1%trifluoroacetic acid), and the purest fractions were combined and lyophilized to afford the titlecompound (0.018 g) as a yellow powder in 14% yield. 1H NMR (ds-DMSO): δ 12.47 (s, 1H), 10.45 (s, 1H), 8.68 (t, 1H, J = 4.5 Hz), 8.09 (s, 1H), 8.01 (s,1H), 7.71 (d, 2H, J = 6.8 Hz), 7.51-7.62 (m, 4H), 7.24-7.41 (m, 5H), 4.80-4.84 (m, 1H), 3.46-3.54(m, 2H). HRMS calculated forC25H2iN403 425.1614 (M+H), found 425.1633.

Example 77: 6-Oxo-2-phenvl-/V-i3-(trifluoromethvl)benzvn-5.6-dihvdro-1 Η-Γ1,21diazepinoF4.5.6- cdlindole-8-carboxamide

Préparation of example 77 from the title compound of Example 49 (0.1 g, 0.291 mmol), 3-(trifluoromethyl)benzylamine (0.102 g, 0.582 mmol), triethylamine (0.081 mL, 0.582 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,/V’,/\/-tetramethyluronium hexafluorophosphate (0.221 g, 0.582 013017 125 mmol) in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an anatogous manner, afforded the titlecompound (0.024 g) as a yellow powder in 18% yield. 1H NMR (d6-DMSO): § 12.49 (s, 1H), 10.48 (s, 1 H), 9.33 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H), 8.06 (s,5 1H), 7.52-7.72 (m, 10H), 4.58 (d, 3H, J = 5.7 Hz). HRMS calculated for CæH^NAFa 463.1382 (M+H), found 463.1391.

Example 78: 6-Oxo-2-phenyl-M-(1-Phenvlethvl)-5,6-dihvdro-1H-n.2)diazepinof4.5.6-cdlindole-8- carboxamide

10 Préparation of example 78 from the title compound of Example 49 (0.103 g, 0.3 mmol), 1-phenylethylamine (0.0727 g, 0.6 mmol), triethylamine (0.084 mL, 0.6 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,/V',/V-tetramethyluronium hexafluorophosphate (0.228 g, 0.6 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the title 15 compound (0.0081 g) as a yellow powder in 6.6% yield. 1H NMR (de-DMSO): δ 12.44 (s, 1H), 10.46 (s, 1H), 9.03 (d, 1H, J = 7.9 Hz), 8.14 (s, 1H), 8.03 (s,1H), 7.71 (d, 2H, J = 7.2 Hz), 7.51-7.62 (m, 4H), 7.41 (d, 2H, J = 7.6 Hz), 7.32 (t, 2H, J = 7.6 Hz),7.22 (t, 1H, J = 7.2 Hz), 5.16-5.25 (m, 1H), 1.51 (d, 3H, J = 6.8 Hz). HRMS calculated for C25H21N4O2 409.1665 (M+H), found 409.1679. 20 Example 79: /V-f1-(4-Fluorophenvl)ethvn-6-oxo-2-phenvl-5.6-dihvdro-1H-f1.21diazepinof4.5.6- cdlindole-8-carboxamide

Préparation of example 79 from the title compound of Example 49 (0.0979 g, 0.285 mmol), 1-(4-fluorophenyl)ethylamine (0.0793 g, 0.57 mmol), triethylamine (0.079 mL, 0.57 mmol), and O-(7- 25 azabenzotriazol-1-yl)-W,W,/V',/V’-tetramethyluronium hexafluorophosphate (0.217 g, 0.57 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0043 g) as a yellow powder in 3.5% yield. 013017 126 1H NMR (d6-DMSO): δ 12.44 (s, 1H), 10.47 (s, 1H), 9.03 (d, 1H, J = 7.9 Hz), 8.13 (s, 1H), 8.02(s, 1H), 7.71 (d, 2H, J = 6.8 Hz), 7.51-7.62 (m, 4H), 7.42-7.47 (m, 2H), 7.12-7.18 (m, 2H), 5.15-5.24 (m, 1 H), 1.50 (d, 3H, J = 7.2 Hz). HRMS calculated for C25H20N4O2F 427.1570 (M+H), found 427.1584. 5 Example 80: /V-(2.3-Dihvdro-1/7-inden-1-vl)-6-oxo-2-phenyl-5.6-dihvdro-1H-f1,2ldiazepinof4,5.6- cdlindole-8-carboxamide

Préparation of example 80 from the tftle compound of Example 49 (0.1 g, 0.291 mmol), 2,3-dihydro-1/-/-inden-1-ylamine (0.0775 g, 0.582 mmol), triethylamine (0.081 mL, 0.582 mmol), and 10 0-(7-azabenzotriazol-1-yl)-A/,/V,/V',/V’-tetramethyluronium hexafiuorophosphate (0.221 g, 0.582mmol) in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0045 g ) as a yellow powder in 3.7% yield. ’H NMR (de-DMSO): δ 12.45 (s, 1H), 10.45 (s, 1H), 9.01 (d, 1H, J = 8.3 Hz), 8.15 (s, 1H), 8.09 (s, 15 1H), 7.71 (d, 2H, J = 6.8 Hz), 7.51-7.62 (m, 4H), 7.18-7.28 (m, 4H), 5.56-5.64 (m, 1H), 2.79-3.06 (m,2H), 1.98-2.46 (m,2H). HRMS calculated for C25H20N4O2F 427.1570 (M+H), found 427.1584.

Example_81;_6-Oxo-2-phenvl-/V-(1.2,3.4-tetrahvdronaphthalen-1-vh-5.6-dihvdro-1F/- f1.21diazepino[4,5.6-cdlindole-8-carboxamide

Préparation of example 81 from the title compound of Example 49 (0.103 g, 0.3 mmol), 1,2,3,4-tetrahydronaphthalen-1-ylamine (0.0883 g, 0.6 mmol), triethylamine (0.084 mL, 0.6 mmol), and O-(7-azabenzotriazol-1-yl)-/y,/y,/V',/V-tetramethyluronium hexafiuorophosphate (0.228 g, 0.6 mmol)in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100% 25 CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0136 g) as a yellow powder in 10% yield. 013017 127 1H NMR (d6-DMSO): § 12.44 (s, 1H), 10.44 (s, 1H), 9.01 (d, 1 H, J = 8.7 Hz), 8.15 (s, 1H), 8.09(s, 1H), 7.71 (d, 2H, J » 6.8 Hz), 7.51-7.62 (m, 4H), 7.10-7.23 (m, 4H), 5.23-5.30 (m, 1H), 2.75-2.81 (m, 2H), 1.96-2.01 (m, 2H), 1.74-1.90 (m, 2H). HRMS calculated for C27H23N4O2 435.1821 (M+H), found 435.1810. 5

Example_82:_/V-i1-Methvl-1-f4-methvlphenvl)ethvn-6-oxo-2-Dhenvl-5.6-dihvdro-1H- i1.2ldiazepinof4.5.6-cc/lindole-8-carboxamide

Préparation of example 82 from the title compound of Example 49 (0.103 g, 0.3 mmol), 1-methÿl- 10 1-(4-methylphenyl)ethylamine (0.0895 g, 0.6 mmol), triethylamine (0.084 mL, 0.6 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,w;/V-tetramethyluronium hexafluorophosphate (0.228 g, 0.6 mmol)in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0304 g) as a yellow powder in 23% yield. 15 ’H NMR (de-DMSO): 8 12.41 (s, 1H), 10.45 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.70(d, 2H, J = 6.80 Hz), 7.51-7.62 (m, 4H), 7.26 (d, 2H, J = 8.3 Hz), 7.08 (d, 2H, J = 7.9 Hz), 2.25 (s,3H), 1.67 (s, 6H). HRMS calculated for C27H25N4O2 437.1978 (M+H), found 437.1987.

Example 83a: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid [2-(3-dimethylaminomethvl-phenvl)- 20 6-oxo-5.6-dihvdro-1W1.2ldiazepinoM.5.6-cdlindol-8-vll-amide

Préparation of example 83a from Intermediate 73(d) of Example 73 (0.11 g, 0.33 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (0.08 g, 0.5 mmol), triethylamine (0.183 mL, 1.32 mmol), O-(7-azabenzotriazol-1-yl)-/V,/V,A/',/V’-tetramethyluronium hexafluorophosphate (0.188 g, 0.5 mmol) 25 and W,N-dimethylformamide (0.2 M, 1.7 mL) was carried out analogously to Example 11. Silica gelchromatography (90:10 to 80:20 CH2CI2/ 2M ammonia in isopropyl alcohol) afforded the titlecompound (0.12 g) as a yellow powder in 76% yield. 013017 10 128

Example 83b: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid f2-(3-dimethvlaminomethvl- phenvl)-6-oxo-5,6-dihvdro-1H-f1.21diazepinor4.5.6-cdlindol-8-vn-amide HCl Sait

The title compound of Example 83a (0.075 g, 0.16 mmol) in dichloromethane (1.0 mL) wastreated with 4M HCl in dioxane (0.043 mL, 0.17 mmol). After concentrating to dryness, the titlecompound (0.08 g) was obtained in quantitative yield. 1H-NMR (d6-DMSO): δ 12.19 (s, 1H), 10.48 (s, 1H), 10.44 (s, 1H), 10.02 (b, 1H), 8.20 (d, 1H, J =1.5 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 7.4 Hz), 7.71-7.59 (m, 4H), 7.34-7.17 (m, 5H), 4.38 (d, 1H, J= 5.0 Hz), 2.78 (d, 6H, J = 4.6 Hz), 2.45-2.37 (m, 1H), 2.14-2.07 (m, 1H), 1.56-1.47 (m, 1H), 1.42-1.35 (m, 1H). HRMS: (M+H+) calcd for C29H28N5O2, 478.2243, found 478.2261.

Example 84: A/-(2-Hvdroxvmethvl-6-oxo-5.6-dihvdro-1/-/-f1.21diazepinof4,5.6-ccflindol-8-vl)- acetamide

MeO.

AcHN

leO^D

XX NHAc

OH (C6H5CN)2PdCI2, Culf-Bu3P, dipea,Dioxane, 70 °C, 9%

AcHN

MeO.

NHAc 84(a) TBDPSCI, imidazole -> DMF, rt, 59%

MeOH, reflux, 69%

84(b) 84(c)

129

Step 1. Préparation of 3,5-Bis-acetylamino-2-(3-hydroxy-prop-1-ynyl)-benzoic acid methyiester 84(a)

Intermediate 6(b) (10 g, 30.4 mmol) of Example 6 and propargyl alcohol were reacted in a manneranalogous to step 1 of Example 73. Intermediate 84(a) (0.85 g) was obtained in 9% yield. 1H-NMR (de-DMSO): δ 10.29 (s, 1H), 9.11 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 5.34 (t, 1H, J = 5.84Hz), 4.38 (d, 2H, J= 5.84 Hz), 3.83 (s, 3H), 2.13 (s, 3H), 2.05 (s, 3H).

Step 2. Préparation of 3,5-Bis-acetylamino-2-[3-(tezf-butyl-diphenyl-silanyloxy)-prop-1-ynylj-benzoic acid methyi ester 84(b)

Chloro-fe/f-butyl-diphenyl-silane (1.3 g, 2 mmol), imidazole (0.54 g, 7.9 mmoi) and Intermediate84(a) (0.48 g, 1.6 mmol) were stirred in Λ/,/V-dimethylformamide (0.2 M, 15 mL) for 0.5 hours at22°C. Methanol was added, the volatiles removed in vacuo, and ethyl aœtate (50 mL) was added.The organic phase was washed with 1N aqueous HCl, brine, dried over MgSO4, filtered, and thevolatiles removed in vacuo. Silica gel chromatography (80:20 ethyl acetate/hexanes) affordedIntermediate 84(b) (0.5 g) in 59% yield. 1H-NMR (de-DMSO): δ 10.31 (s, 1H), 9.18 (s, 1H), 8.25 (d, 1H, J = 1.8 Hz), 8.00 (d, 1H, J = 1.8Hz), 7.74-7.68 (m, 4H), 7.50-7.41 (m, 6H), 4.67 (s, 2H), 3.81 (s, 3H), 2.05 (s, 6H), 1.01 (s, 9H).LCMS: (M-H+) 541.1

Step 3. Préparation of 6-Acetylamiiio-2-(fert-butyl-diphenyl-silanyloxymethyl)-1H-indole-4-carboxylic acid methyi ester 84(c)

In a manner analogous to step 5 of Example 5, from Intermediate 84(b) (0.46 g, 0.84 mmol) wasreacted to provide Intermediate 84(c) (0.24 g) in 57% yield. 1H-NMR (de-DMSO): δ 11.36 (s, 1H), 10.04 (s, 1H), 8.25 (s, 1H), 7.78 (d, 1H, J = 1.5 Hz), 7.74-7.66 (m, 4H), 7.50-7.41 (m, 6H), 6.72 (s, 1H), 4.85 (s, 2H), 3.87 (s, 3H), 2.06 (s, 3H), 1.03 (s, 9H).LCMS: (M-H+) 499.1

Step 4. Préparation of W-[2-(ferf-Butyl-dîphenyl-silanyloxymethyl)-6-oxo-5,6-dîhydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl]-acetamide 84(d) in a manner analogous to steps 4 and 5 of Example 3, Intermediate 84(c) (0.2 g, 0.4 mmol) wasformylated and cyclized to provide Intermediate 84(d) (0.14 g) in 69% yield. LCMS: (M-H+) 509.1.

Step 5. Préparation of Title Compound: /V-(2-Hydroxymethyl-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-acetamide

To a solution of Intermediate 84(d) (0.085 g, 0.17 mmol) in tetrahydrofuran (0.1 M, 1.6 mL) wasadded a 1M solution of tefra-butyl ammonium fluoride in tetrahydrofuran (0.184 mL, 0.18 mmol).The mixture was stirred at 22 °C for 2 hours, and the yellow soiid was collected by filtration and 013017 130 washed with methanol (5.0 mL) and diethyl ether (5.0 mL) to afford the title compound (0.029 g)in 64% yield. 1H-NMR (ds-DMSO): δ 11.74 (s, 1H), 10.17 (s, 1H), 10.02 (s, 1 H), 8.04 (d, 1H, J = 1.3 Hz), 7.54(s, 1 H), 7.53 (s, 1 H), 5.47 (dd, 1 H, J = 5.5, 5.5 Hz), 4.68 (d, 2H, J = 5.4 Hz). 5 LCMS: (M+H+) 273.1. HRMS: (M+H+) calcd for C^H^Os, 273.1001, found 273.0988.

Example 85: Acetic acid 3-f6-oxo-8-f(Y1R, 2R)-2-phenvl-cvclopropanecarbonvl)-amino1-5.6- dihvdro-1 H-H ,21diazepinof4.5.6-cdlindol-2-vl)-benzvl ester

1. POCI3. DMF, CH2CI2 2. NH2NH2,AcOH, MeOHMeOH, reflux, 66%

10 Step 1. Préparation of 2-(3-Hydroxymethyl-phenyl)-6-[(1R,2R)-(2-phenyl-cyclopropanecarbonyl)-aminoî-1H-indole-4-carboxylic acid methyl ester 85(a)

Intermediate 73(c) from Example 73 (1.8 g, 5 mmol) was dissolved in methanol (22 mL). 4M HClin dioxane (22 mL, 75 mmol) was carefully added, and the solution was heated at 90 °C for 1hour. After cooling to 22 °C, the volatiles were removed in vacuo giving 6-amino-2-(3- 15 hydroxymethyl-phenyl)-1H-indole-4-carboxylic acid methyl ester which was then combined with(1R,2R)-2-phenyl-cyclopropanecarboxylic acid (2 g, 12.5 mmol), triethylamine (3.5 mL, 25 mmol),and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (4.7 g, 12.5mmol) in /V,/V-dimethylformamide (0.2 M, 25 mL) and stirred at 22 °C for 12 hours. Volatiles wereremoved in vacuo and the crude mixture dissolved in methanol (25 mL, 0.2 M) was treated with 20 K2CO3 (1.38 g, 10 mmol) for 1 hour at 22 °C. Excess K2CO3 was removed by filtration, and acetic 013017 131 acid (2 drops) was added to the filtrate. Following filtrate évaporation, the residue was subjectedto silica gel chromatography (90:10 to 100:0 ethyl acetate/hexane) which provided Intermediate85(a) (1.1 g, 2.5 mmol) in 50% yield. 1H-NMR (de-DMSO): δ 11.83 (s, 1H), 10.41 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.75(d, 1H, J = 7.9 Hz), 7.43 (dd, 1H, J = 7.7, 7.5 Hz), 7.35-7.17 (m, 7H), 5.30 (dd, 1H, J = 5.8, 5.6Hz), 4.59 (d, 2H, J = 5.4 Hz), 2.45-2.36 (m, 1H), 2.14-2.07 (m, 1H), 1.58-1.47 (m, 1H), 1.42-1.34'(m, 1H). HRMS: (M+H+) calcd for C27H25N2O4,441.1828, found 441.1814.

Step 2. Préparation of 2-(3-Acetoxymethyi-phenyl)-6-[(1R,2R)-(2-phenyl-cyclopropanecarbonyl)-amino]-1W-indoie-4-carboxylic acid methyl ester 85(b)

To a suspension of Intermediate 85(a) (1.1 g, 2.3 mmol) in ethyl acetate (22 mL, 0.1 M) wasadded 4-(dimethylamino)-pyridine (0.28 g, 2.3 mmol) and acetic anhydride (0.47 g, 4.6 mmol).The mixture was stirred at 22 °C for 1 h, and the volatiles were removed in vacuo. Silica gelchromatography (70:30 to 100:0 ethyl acetate/Hexanes) provided Intermediate 85(b) (1.1 g, 2.3mmol) in quantitative yield. 1H-NMR (de-DMSO): δ 11.85 (s, 1H), 10.43 (s, 1H), 8.26 (s, 1H), 7.92-7.81 (m, 3H), 7.49 (dd, 1H, J =7.7, 7.6 Hz), 7.37-7.13 (m, 7H), 5.15 (s, 2H), 3.92 (s, 3H), 2.45-2.36 (m, 1H), 2.14-2.07 (m,1H), 1.58-1.47 (m, 1H), 1.42-1.34 (m, 1H). HRMS: (M+H+) calcd for CZ9H27N2O5,483.1920, found 483.1945.

Step 3. Préparation of Title Compound: Acetic acid 3-{6-oxo-8-[((1R, 2R)-2-phenyl- cyclopropanecarbonyl)-amino]-5,6-dihydro-'lH-[1,2]diazepino[4,5,6-cd]indol-2-yl}-benzyl ester

In a manner analogous to steps 4 and 5 of Example 3, Intermediate 85(b) (0.75 g, 1.56 mmol)was formylated and cyclized. Purification by silica gel chromatography (40:60 to 100:0 ethylacetate/ Hexanes) afforded the title compound (0.505 g, 1.03 mmol) as a yeltow powder in 66%yield. 1H-NMR (de-DMSO): δ 12.13 (s, 1H), 10.44 (s, 1H), 10.39 (s, 1H), 8.16 (d, 1H, J = 1.5 Hz), 7.68-7.45 (m, 6H), 7.34-7.17 (m, 5H), 5.18 (s, 2H), 2.50-2.34 (m, 1H), 2.14-2.07 (m, 4H), 1.58-1.47 (m, 1 H), 1.43-1.35 (m, 1 H). HRMS: (M+H+) calcd for CæHæN^, 493.1876, found 493.1882.

Anal. Calcd. for C29H24N4O4 · 0.4 H2O: C, 69.70; H, 5.00; N, 11.21. Found: C, 69.71; H, 5.03; N,11.33.

Example 86: (1R, 2R)-2-Phenvl-cvclopropanecarboxvlic acid Î2-(3-hvdroxvmethvl-phenvl)-6-oxo- 5.6-dihvdro-1H-f1.2ldiazepinof4.5.6-cd1indol-8-vl1-amide 013017 132

HN—N

HO

The title compound of Example 85 (0.288 g, 0.58 mmol) and K2CO3 (0.161 g, 1.17 mmol) werestirred in methanol (0.2 M, 1.7 mL) and tetrahydrofuran (0.2 M, 1.7 mL) for 1.5 hours at 22 °C.After the solution was filtered and acidified with two drops of glacial acetic acid, the volatiles were 5 removed in vacuo. Siiica gel chromatography (40:60 to 0:100 hexane/ethyl acetate) afforded thetitle compound (0.26 g) as a yellow powder in 95% yield. 1H-NMR (d6-DMSO): δ 12.11 (s, 1H), 10.43 (s, 1H), 10.36 (s, 1H), 8.15 (d, 1H, J= 1.0 Hz), 7.64(d, 1H, J= 1.0 Hz), 7.61 (s, 1H), 7.55-7.17 (m, 9H), 5.35 (dd, 1H, J= 5.8, 5.6 Hz), 4.60 (d, 2H, J =5.6 Hz), 2.45-2.36 (m, 1H), 2.14-2.07 (m, 1H), 1.58-1.47 (m, 1H), 1.42-1.34 (m, 1H). 10 LCMS: (M-H*) 449.1.

Anal. Calcd. for C27H22N4O3 · 0.1 CH2CI2 · 0.1 02Η502(ΧΗ3: C, 70.61; H, 4.96; N, 11.98. Found:C, 70.01; H, 4.95; N, 11.95.

Example 87: A/-(2.4-Difluorobenzvl)-6-oxo-2-phenvl-5,6-dihydro-1H-f1.21diazepinof4,5,6-cc/lindole- 8-carboxamide 15

HN—N

Préparation of example 87 from the title compound of Example 49 (0.102 g, 0.297 mmol), 2,4-difluorobenzylamine (0.085 g, 0.594 mmol), triethylamine (0.083 mL, 0.594 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,W’,/V-tetramethyluronium hexafluorophosphate (0.226 g, 0.594 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100% 20 CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0044 g) as a yellow powder in 3.4% yield. 1H NMR (dB-DMSO): 8 12.48 (s, 1H), 10.48 (s, 1H), 9.20 (t, 1H, J = 5.5 Hz), 8.13 (s, 1H), 8.05 (s,1H), 7.71 (d, 2H, J= 7.2 Hz), 7.52-7.62 (m, 4H), 7.40-7.47 (m, 1H), 7.16-7.25 (m, 1H), 7.03-7.10(m, 1H), 4.49 (d, 2H, J= 5.3 Hz). 25 HRMS calculated for C^HnlÎAFg 431.1320 (M+H), found 431.1324. 013017

Example 88: 4-f2-(6-Qxo-2-phenvl-5,6-dihvdro-1/7-f1.21diazepinof4.5,6-cdlindol-8-vlcarbamoyl)- ethyH-piperidine-1-carboxylic acid ferf-butyl ester 133

Préparation of example 88 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141mmol), 4-(2-carboxy-ethyl)-piperidine-1-carboxylic acid ferf-butyl ester (43 mg, 0.169 mmol),triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 8:5:2 CH2CI2:hexane:methanol), also in an analogous manner,afforded the title compound (62 mg, 0.120 mmol) as a yeilow powder in 85% yield. 1H NMR (d6-DMSO): δ 12.15 (s, 1H), 10.37 (s, 1H), 10.06 (s, 1H), 8.20 (s, 1 H), 7.70-7.46 (m, 7H),3.96-3.87 (m, 2H), 2.75-2.63 (m, 2H), 2.42-2.34 (m, 2H), 1.72-1.55 (m, 5H), 1.40 (S, 9H), 1.06-0.98 (m, 2H). LCMS: (M+H+) 416.3, (M+Na+) 538.3.

Example 89: (E)-/V-(6-Oxo-2-phenvl-5.6-dihvdro-1/V-ft.21diazepinof4,5,6-cdIindol-8-vl)-3-phenvl- acrvlamide

Préparation of example 89 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128mmol), (E)-3-phenyl-acrylic acid (23 mg, 0.154 mmol), triethylamine (0.054 mL, 0.384 mmol), andO-(7-azabenzotriazol-1-yl)-A/,/V,/V',/V-tetramethyluronium hexafluorophosphate (59 mg, 0.154mmol) in CH2CI2 (0.4 mL) and /V,A/-dimethylformamide (0.4 mL) was carried out analogously toExample 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogousmanner, after a final trituration with methanol afforded the title compound (47 mg, 0.116 mmol) asa yeilow powder in 90% yield. 1H NMR (d6-DMSO): δ. 12.14 (s, 1H), 10.43 (s, 1H), 10.40 (s, 1H), 8.38 (s, 1H), 7.71-7.40 (m,13H), 6.87 (d, 1H, J =16.2 Hz). LCMS: (M+H+) 407.1, (M+Na+) 429.0, (M-H‘) 405.2.

Anal. Calcd. for C26H18N4O2'2.7 HZO: C, 65.98; H, 5.18; N, 12.31.

Found: C, 65.62; H, 4.63; N, 12.10. 013017

Example 90: (2E,4E)-Hexa-2,4-dienoic acid (6-oxo-2-phenvl-5,6-dihvdro-1H-f1.21diazeDinor4.5.6- ctflindol-8-vl)-amide 134

Préparation of example 90 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131mmol), (2E,4E)-hexa-2,4-dienoic acid (18 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/\/,/\/',A/'-tetramethyluronium hexafluorophosphate (60mg, 0.157 mmol) in CH2CI2 (0.4 mL) and A/,W-dimethylformamide (0.4 mL) was carried outanalogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also inan analogous manner, after a final trituration with methanol affoFded the title compound (8 mg,0.022 mmol) as a yellow powder in 16% yield. 1H NMR (d6-DMSO): § 12.13 (s, 1H), 10.38 (s, 1 H), 10.21 (s, 1H), 8.30 (s, 1H), 7.71-7.48 (m, 7H),7.15 (m, 1H), 6.38-6.07 (m, 3H), 1.84 (d, 3H, J= 5.8 Hz). LCMS: (M+H+) 371.1, (M+Na+) 393.0.

Example 91: (2R)-2-Amino-2-cvclohexyl-A/-f6-oxo-2-phenvl-5.6-dihvdro-1H-f1,2ldiazepinof4.5.6-

The title compound of Example 59 (210mg, 0.41 mmol) was treated with 4M HCl in dioxane andallowed to stir tightly capped as a slurry for about 4 hours after which the volatile componentswere evaporated and diethyl ether was added and evaporated several times. The resulting solidswere dissolved in methanol, precipitated with diethyl ether, and collected to afford the titlecompound (161 mg, 0.36 mmol) as a yellow powder in 87% yield. 1H NMR (d6-DMSO): δ 12.27 (s, 1H), 10.83 (s, 1H), 10.44 (s, 1H), 8.36 (br s, 2H), 8.13 (s, 1H),7.78-7.64 (m, 3H), 7.63-7.48 (m, 4H), 3.81 (brs, 1H), 1.91-1.58 (m, 6H), 1.31-1.00 (m, 5H). LCMS: (M+H+) 416.1,(M+Na+) 438.2.

Anal. Calcd. for C24H25N5O2 ’ 1.5 HCl · 2.0 H2O: C, 56.94; H, 6.07; N, 13.84.

Found:C, 57.20; H, 6.01; N, 13.57. 013017

Example 92: /V-(6-Ôxo-2-phenvl-5.6-dihvdro-1H-l't,21diazepinof4,5.6-cdlindol-8-vl)-3-piperidin-4- vl-propionamide; oompound with trifluoro-acetic acid 135

10

Préparation of example 92 from title compound of Example 88 (52 mg, 0.101 mmol) and 45%TFA in CH2CI2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogousmanner, afforded the title compound (50 mg, 0.084 mmol) as a yellow powder in 82% yield. 1H NMR (de-DMSO): δ 12.07 (s, 1H), 10.38 (s, 1H), 10.09 (s, 1H), 8.45 (br s, 1H), 8.17 (s, 1H),7.70-7.44 (m, 7H), 3.31-3.20 (m, 2H, partially obscurred), 2.93-2.76 (m, 2H), 2.41-2.31 (m, 2H),1.91-1.76 (m, 2H), 1.64-1.49 (m, 3H), 1.38-1.19 (m, 2H).

Anal. Calcd. for C24H25NSO2 1.5 TFA 0.8 H2O: C, 53.64; H, 4.75; N, 11.58.

Found: C, 53.59; H, 4.74; N, 11.55.

Example 93: 6-Oxo-2-phenvl-/V-f(1ffl-1-phenvlet)ivl1-5.6-dihvdro-1 W1.21diazepinoi4,5,6- cdlindole-8-carboxamide

15 Préparation of example 93 from the title compound of Example 49 (0.105 g, 0.306 mmol), (1R)-1-phenylethylamine (0.0742 g, 0.612 mmol), triethylamine (0.085 mL, 0.612 mmol), and O-(7-azabenzotriazol-1-yl)-W,/\/,W’,W’-tetramethyluronium hexafluorophosphate (0.233 g, 0.612 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O cantaining 0.1% trifluoroacetic acid), also in an analogous manner, afforded the title 20 compound (0.0235 g) as a yellow powder in 19% yield. 1H NMR (d6-DMSO): δ 12.44 (s, 1H), 10.46 (s, 1H), 9.03 (d, 1H, J = 7.9 Hz), 8.14 (s, 1H), 8.04 (s,1H), 7.70 (d, 2H, J= 6.8 Hz), 7.51-7.62 (m, 4H), 7.42 (d, 2H, J= 7.2 Hz), 7.30-7.36 (m, 2H), 7.20-7.24 (m, 1H), 5.16-5.25 (m, 1H), 1.50 (d, 3H, J = 7.2 Hz). HRMS calculated for C25H21N4O2 409.1665 (M+H), found 409.1666. 013017

Example 94: 6-Oxo-2-phenvl-/\/-i(t S)-1-phenvlethvH-5.6-dihydro-1H-f1.2ldiazepinof4,5.6- cdlindole-8-carboxamide 136

Préparation of example 94 from the title compound of Example 49 (0.0976 g, 0.284 mmol), (1S)- 5 1-phenylethylamine (Q.0688 g, 0.568 mmol), triethylamine (0.079 mL, 0.568 mmol), and O-(7-azabenzotriazol-1-yI)-/V,A/,/V',A/-tetramethyluronium hexafluorophosphate (0.216 g, 0.568 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0197 g) as a yellow powder in 17% yield. 10 1H NMR (d6-DMSO): δ 12.44 (s, 1H), 10.46 (s, 1 H), 9.04 (d, 1H, J = 7.9 Hz), 8.14 (s, 1H), 8.03 (s,1H), 7.70 (d, 2H, J = 8.3 Hz), 7.51-7.62 (m, 4H), 7.42 (d, 2H, J = 7.2 Hz), 7.30-7.36 (m, 2H), 7.20-7.24 (m, 1H), 5.16-5.25 (m, 1H), 1.50 (d, 3H, J = 7.2 Hz). HRMS calculated for C25H21N4O2 409.1665 (M+H), found 409.1666.

Example 95: A/-i1-(4-Chlorophenvhethvll-6-oxo-2-phenvl-5,6-dihvdro-1 rt-H.21diazepino[4.5.6- 15 ccnindole-8-carboxamide

Préparation of example 95 from the title compound of Example 49 (0.104 g, 0.303 mmol), 1-(4-chlorophenyl)ethylamine (0.0943 g, 0.606 mmol), triethylamine (0.084 mL, 0.606 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/\/',/V’-tetramethyluronium hexafluorophosphate (0.23 g, 0.606 mmol) 20 in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0025 g) as a yellow powder in 1.9% yield. 1H NMR (ds-DMSO): δ 12.45 (s, 1H), 10.47 (S, 1H), 9.06 (d, 1H, J = 7.9 Hz), 8.14 (s, 1H), 8.03 (s,1H), 7.70 (d, 2H, J = 7.9 Hz), 7.51-7.62 (m, 4H), 7.38-7.44 (m, 4H), 5.13-5.22 (m, 1H), 1.49 (d, 25 3H, J = 7.2 Hz). HRMS calculated for C25H20N4O2CI 443.1275 (M+H), found 443.1265. 0130Π

Example 96: A/-f1-(4-Hvdroxvphenvl)ethvl1-6-oxo-2-phenyl-5.6-dihvdro-1/-/-f1,2ldiazepinof4.5,6- cdlindole-8-carboxamide 137

Préparation of example 96 from the title compound of Example 49 (0.104 g, 0.303 mmol), 1-(4-hydroxyphenyl)ethylamine (0.0831 g, 0.606 mmol), triethylamine (0.084 mL, 0.606 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/V,W’,/V-tetramethyluronium hexafluorophosphate (0.23 g, 0.606 mmol)in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0205 g) as a yellow powder in 16% yield. ’H NMR (d5-DMSO): δ 12.42 (s, 1H), 10.45 (s, 1H), 9.21 (br s, 1 H). 8.91 (d, 1H, J = 8.3 Hz), 8.11(s, 1H), 8.02 (s, 1H), 7.70 (d, 2H, J = 6.8 Hz), 7.51-7.61 (m, 4H), 7.21 (d, 2H, J = 8.3 Hz), 6.71 (d,2H, J= 8.3 Hz), 5.08-5.16 (m, 1H), 1.46 (d, 3H, J = 7.2 Hz). HRMS calculated for C25H21N4O3 425.1614 (M+H), found 425.1626.

Example 97: 2.3-Difluôro-/V-(6-oxo-2-phenvl-5,6-dihvdro-1 Η-Γ1,21diazepinol4.5.6-cdlindol-8-vh- benzamide

Préparation of example 97 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128mmol), 2,3-difluoro-benzoic acid (24 mg, 0.154 mmol), triethylamine (0.054 mL, 0.384 mmol), and0-(7-azabenzotriazol-1-yl)-W,/tf,/V’,/V-tetrarnethyluroniurn hexafluorophosphate (59 mg, 0.154mmol) in CH2CI2 (0.4 mL) and /V,/V-dimethylformamide (0.4 mL) was carried out analogously toExample 11. Silica gel chromatography (eluted with 2:1 hexane:acetone increasing to 1:1hexane:acetone), also in an analogous manner, afforded the title compound (24 mg, 0.058 mmol)as a yellow powder in 45% yield. ’H NMR (ds-DMSO): δ 12.20 (s, 1H), 10.72 (s, 1H), 10.42 (s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.72-7.45 (m, 8H), 7.37 (m, 1H). LCMS: (M+H+) 417.0, (M+Na+) 439.1. 013017

Example 98: 2,3-Dimethvl-A/-f6-oxo-2-phenvi-5,6-dihydro-1/d-f1.2ldiazepinof4.5.6-cdlindol-8-vl)- benzamide 138

HN-N

Préparation of example 98 from the title compound of Example 7 (hydrochloride) (42 mg, 0.1345 mmol), 2,3-dimethyl-benzoic acid (24 mg, 0.161 mmol), triethylamine (0.056 mL, 0.402 mmol),and O-(7-azabenzotriazol-1-yl)-W,/V,/V'/V'-tetramethyluronium hexafiuorophosphate (61 mg, 0.161mmol) in CH2CI2 (0.4 mL) and /V,/V-dimethylformamide (0.4 mL) was carried out analogously to

Example 11. The mixture was stirred as a thick slurry and additional 2,3-dimethyl-benzoic acid (12mg, 0.08 mmol) and 0-(7-azabenzotriazol-1-yl)-W,A/,W',A/-tetramethyluroniiim 10 hexafiuorophosphate (30 mg, 0.08 mmol) were added after 48 hours to drive the reaction tocompletion. The mixture was filtered to collect the solids which were then washed with methanol.After drying the solids under high vacuum, the title compound (32 mg, 0.078 mmol) was obtainedas a yellow powder in 58% yield. 1H NMR (d6-DMSO): § 12.14 (s, 1H), 10.47 (s, 1H), 10.39 (s, 1H), 8.25 (s, 1 H), 7.86 (m, 1H), 7.72- 15 7.66 (m, 2H), 7.63-7.49 (m, 4H), 7.33-7.25 (m, 2H), 7.21 (m, 1 H), 2.31 (s, 3H), 2.29 (s, 3H). LCMS: (M+H+) 409.1, (M+Na+) 431.1.

Example 99: 3-Fluoro-2-methvl-/V-(6-oxo-5.6-dihvdro-1 W1,21diazepinor4.5.6-cdiindol-8-vl)- benzamide

HN-N 20 Préparation of example 99 from title compound of Example 2 (21 mg, 0.105 mmol), 3-fluoro-2-methyl-benzoic acid (19 mg, 0.126 mmol), triethylamine (0.044 mL, 0.315 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,W’,/V’-tetramethyluronium hexafiuorophosphate (48 mg, 0.126 mmol) inCH2CI2 (0.2 mL) and /V,/V-dimethylformamide (0.2 mL) was carried out analogously to Example11. The mixture was stirred as a thick slurry and additional 3-fluoro-2-methyl-benzoic acid (11 mg, 25 0.07 mmol) and 0-(7-azabenzotriazol-1-yl)-/\/,/\/,W’,/V-tetramethyluronium hexafiuorophosphate (27 mg, 0.07 mmol) were added after 24 hours to drive the reaction to completion. Purification,also in an analogous manner, except that it required two successive silica gel chromatographies 013017 139 (both eluted with 2:1 hexane:acetone increasing to 1:1 hexane:acetone) afforded the titlecompound (14 mg, 0.042 mmol) as a yellow powder in 40% yield. M NMR (d6-DMSO): δ 11.79 (s, 1 H), 10.50 (s, 1 H), 1,0.25 (s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.60(s, 1 H), 7.49 (s, 1H), 7.46-7.17 (m, 3H), 2.30 (s, 3H). LCMS: (M+H+) 337.1, (M+Na+) 359.1.

Example 100: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid (6-oxo-5,6-dihvdro-1H- ri.21diazepino[4.5.6-cd]indol-8-yl)-amide

POCI3. DMFCH2CI2, 66%

NH2NH2, AcOH, MeOH

MeOH, reflux, S7%

HN-N

Step 1. Préparation of 6-[((1R,2R)-2-Phenyl-cyclopropanecarbonyl)-amino]-1H-indole-4-10 carboxylic acid methyi ester 100(a)

Préparation of intermediate 100(a) from Intermediate 2(b) of Example 2 (111 mg, 0.49 mmol),(1R,2R)-2-phenyl-cyclopropanecarboxylic acid (119 mg, 0.73 mmol), triethylamine (0.273 mL,1.96 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/\/’,A/-tetramethyluronium hexafluorophosphate(278 mg, 0.73 mmol) in CH2CI2 (0.4 mL) and /V,A/-dimethylformamide (0.4 mL) was carried out 15 analogously to Example 11 Extractive work-up from ethyl acetate and saturated aqueousNaHCO3 afforded crude Intermediate 100(a) (222 mg) as a tan solid which was carried on withoutpurification.

Step 2. Préparation of 3-Formyl-6-[((1R,2R)-2-phenyl-cyclopropanecarbonyl)-amino]-1W-indole-4-carboxylic acid methyi ester 100(b) 20 Intermediate 100(a) (214 mg) was dissolved in CH2CI2 (3 mL) and Λ/,/V-dimethylformamide (0.2mL) and treated with Vilsmeier reagent (0.147 mL) in a manner similar to that described forExample 3, Step 4. Upon addition, an immédiate precipitate formed causing a thick slurry.Additional CH2CI2 (5.0 mL) and /V,A/-dimethylformamide (0.2 mL) was added to facilitate stirring.Additional Vilsmeier reagent (0.147 mL) was also added. After c.a. 10 min, hexane was added, 25 and the solids were allowed to settle. After decanting the supernatant, additional hexane wasadded and the trituration was repeated- discarding both triturâtes. To the remaining solids,methanol (8 mL) was added along with K2CO3 (750 mg, 5.43 mmol) and H2O (4 mL), and the 013017 140 mixture was allowed to stir. After c.a. 30 min, ethyl acetate was added and the K2CO3/H2Oaggregates were removed by decanting the product away in solution. The solvents were thenreduced in volume, additional ethyl acetate was added, and the product was subjected toextractive work-up to afford Intemediate 100(b) (117 mg, 0,32 mmol) as a brownish powder inabout a 66% combined, crude yield over steps 1 and 2.

Step 3. Préparation of Titie Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1/V-[1,2]diazepjno[4,5,6-ctf|indol-8-yl)-amide

Intermediate 100(b) (105 mg), acetic acid (0.048 mL, 0.84 mmol) and H2NNH2 ' H2O (0.084 mL,1.74 mmol) in anhydrous methanol (4.4 mL) were refluxed in manner similar to that described forExample 3, Step 5. The crude product was purified on silica gel'eluting with 2:1 then 1:1hexane:acetone to afford the titie compound (61 mg, 0.17 mmol) in about a 57% yield for the laststep. 1H NMR (d6-DMSO): δ 11.74 (s, 1H), 10.38 (s, 1H), 10.23 (s, 1H), 8.13 (s, 1H), 7.60-7.53 (m, 2H),7.46 (s, 1 H), 7.35-7.26 (m, 2H), 7.24-7.15 (m, 3H), 2.38 (m, 1H), 2.08 (m, 1H), 1.50 (m, 1H), 1.36(m, 1H). LCMS: (M+H+) 345.2, (M+Na+) 367.1.

Anal. Calcd. for C20H16N4O2 · 0.6 H2O 0.1 methanol ' 0.1 CH2CI2: C, 66.13; H, 4.89; N, 15.27.Found: C, 66.19; H, 5.03; N, 15.07.

Altenative Method for the Préparation of Example 100.

Préparation of example 100 from the titie compound of Example 2 (3.0 g, 12.7 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (2.36 g, 14.6 mmol) (prepared as described by A. Thurkauf, etal. (2000) J. Med. Chem. 43:3923-3932), triethylamine (8.8 mL, 63.4 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,/V’,/V-tetramethyluronium hexafluorophosphate (5.3 g, 14.5 mmol) inΛ/,/V-dimethylformamide (30.0 mL, 0.4 M) was carried out analogously to Example 11. Silica gelchromatography (5:50:45 methanol/ethyl acetate/CH2CI2), also in an analogous manner, affordedthe titie compound (3.67 g, 10.7 mmol) as a yellow powder in 84% yield.

Example_101:_/V-f2-Hvdroxv-2-(3-hvdroxyphenv0ethvll-6-oxo-2-phenvl-5.6-dihvdro-1/·/- ri.21diazepinof4.5.6-ccllindole-8-carboxamide

HN-N HO.

Préparation of example 101 from the titie compound of Example 49 (0.238 g, 0.693 mmol), 2-hydroxy-2-(3-hydroxyphenyl)ethylamine hydrochloride (0.264 g, 1.39 mmol), triethylamine (0.29 013017 141 mL, 2.08 mmol), and 0-(7-azabenzotriazol-1-yl)-N,N,/V’,W-tetramethyluroniumhexafluorophosphate (0.528 g, 1.39 mmol) in DMSO (2 mL) was carried out analogously toExample 76. Préparative HPLC (20-100% CH3CN/H2O containing 0.1% trifluoroacetic acid), alsoin an analogous manner, afforded the title compound (0.0414 g) as a yellow powder in 14% yield. 5 1H NMR (d6-DIVISO): δ 12.47 (s, 1H), 10.45 (s, 1H), 9.27 (brs, 1H), 8.68 (t, 1H, J = 5.7 Hz), 8.10(s, 1H), 8.02 (s, 1H), 7.71 (d, 2H, J = 7.2 Hz), 7.51-7.62 (m, 4H), 7.08-7.13 (m, 1H), 6.76-6.81 (m,2H), 6.61-6.64 (m, 1H), 4.70-4.74 (m, 1H). HRMS calculated for C25H21N4O4 441.1563 (M+H), found 441.1543.

Example 102: Methvl-6-oxo-2-phenvl-1,3,5.6-tetrahvdron ,21oxazepinoi6,5.4-cdlindole-8- 10 carboxvlate

102(d)

Step 1. Préparation of 1-terf-butyl-4,6-dimethyl-3-formyl-2-phenyl-1H-indole-1,4,6-15 tricarboxylate 102(a)

To a solution of Intermediate 39(e) of Example 39 (2.25 g, 6.7 mmol), and di-ferf-butyl dicarbonate(11.68 g, 54 mmol) in 150 ml of tetrahydrofuran was added a 60% suspension of NaH in mineraioil (1.60 g, 40 mmol). The reaction mixture was stirred at room température for 1 hour. Extractivework-up from ethyl acetate and saturated aqueous NaHC03 followed by silica gel chromatography 20 afforded Intermediate 102(a) (1.97 g), in 67% yield. 01301 142 1H NMR (d6-DMSO): δ 9.56 (s, 1 H), 8.96 (s, 1H), 8.08 (s, 1 H), 7.70-7.50 (m, 5H), 3.93 (s, 3H),3.83 (S, 3H), 1.20 (s, 9H).

Step 2. Préparation of 1-(fert-Butoxycarbonyl)-3-(hydroxymethyl)-6-(methoxycarbonyl)-2-phenyl-1H-indole-4-carboxylic acid 102(b) 5 Intermediate 102(a) (1.95 g) was dissolved in methanol (200 mL) and NaBH4 (1.70 g) was addedand stirred for 15 min. After removing solvent, silica gel chromatography afforded Intermediate102(b) (1.81 g) in 92% yield. 1H NMR (d6-DMSO): δ 8.97 (d, 1H, J = 1.5 Hz), 8.10 (d, 1H, H=1.5 Hz), 7.35-7.55 (m, 5H), 4.61 (t,1H, J = 5.1 Hz), 4.41 (d, 2H, J = 5.0 Hz), 3.92 (s, 3H), 3.87 (s, 3H), 1.16 (s, 9H). 10 Step 3. Préparation of 1-ie/f-Butyl-4,6-dimethyl-3-(chloromethyl)-2-phenyl-1H-indole-1,4,6-tricarboxyiate 102(c)

To a solution of Intermediate 102(b) (1.6B g, 3.8 mmol) and CCI4 (3.50 g, 23 mmoi) in 20 ml ofdichloromethane was added Ph3P (2.42 g, 9.2 mmol). The reaction mixture was stirred at roomtempérature for 24 hours. The reaction mixture was concentrated, and residue was purified using 15 silica gel chromatography to afford Intermediate 102(c) (1.53 g) in 87% yield. 1H NMR (d6-DMSO): δ 8.97 (d, 1H, J= 1.5 Hz), 8.10 (d, 1H, J = 1.5 Hz), 7.35-7.55 (m, 5H), 4.61(t, 1H, J= 5.1 Hz), 4.41 (d, 2H, J= 5.0 Hz), 3.92 (s, 3H), 3.87 (s, 3H), 1.16 (s, 9H).

Step 4. Préparation of 1-fert-Butyl 4,6-dimethyl 3-{[(1,3-dioxo-1.3-dihydro-2/7-isoindol-2-yl)oxy]methyl}-2-phenyl-1 H-indole-1,4,6-tricarboxylate 102(d) 20 A mixture of Intermediate 102(c) (0.23 g, 0.5 mmol), W-hydroxyphthalimide (0.24 g, 1.5 mmol) andNa2CO3 (0.32 g, 3 mmol) was stirred in anhydrous DMSO (10 mL) at room température overnight.Extractive work-up from ethyl acetate, followed by silica gel chromatography afforded Intermediate102(d) (0.16 g) in 55% yield. 1H NMR (de-DMSO): δ 9.02 (d, 1H, J = 1.1 Hz), 8.31 (d, 1H, H=1.1 Hz), 7.75-7.82 (m, 2H), 7.64- 25 7.71(m, 2H), 7.39 (t, 1H, J = 7.6 Hz), 7,26 (t, 2H, J = 7.6), 7.18 (d, 2H, J = 7.8 Hz), 5.32 (s, 2H), 3.94 (s, 3H), 8.92 (s, 3H), 1.11 (s, 9H).

Step 5. Préparation of Titie Compound Methyl-6-oxo-2-phenyl-1,3,5,6-tetrahydro[1,2]oxazepino[6,5,4-cd]indole-8-carboxylate A mixture of Intermediate 102(d) (0.15 g, 0.26 mmol) and hydrazine (0.20 g, 6.3 mmol) in 30 methanol (15 mL) was refluxed for 2 hours. After solvent évaporation, the residue was mixed withCH2CI2 (15 ml) and trifluoroacetic acid (7.5 ml) and stirred for 2 hours. After solvent removal, theresidue was subjected to reverse-phase préparative HPLC affording the titie compound (34.8 mg)in 42% yield. 1H NMR (de-DMSO): δ 12.20 (s, 1H), 11.23 (s, 1H), 8.30 (d, 1H, J = 1.2 Hz), 8.21 (d, 1H, H=1.2 35 Hz), 7.40-7.75 (m, 5H), 5.44 (d, 1 H, J = 14.7 Hz), 5.22 (d, 1 H, J = 14.7 Hz), 3.92 (s, 3H). LCMS (M++1): 323.0 013017

Example 103: /V-(4-Fluorobenzyl)-6-oxo-2-phenvl-5.6-dihvdro-1 H41,21diazepino[4,5.6-ctflindole- 8-carboxamide 143

HN—N

Préparation of example 103 from the title compound of Example 49 (0.108 g, 0.314 mmol), 4-fluorobenzylamine (0.079 g, 0.628 mmol), triethylamine (0.088 mL, 0.628 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,A/',/V'-tetramethyluronium hexafluorophosphate (0.239 g, 0.628 mmol) inDMSO (2 mL) was carried out analogously to Example 78. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0121 g) as a yellow powder in 9.3% yield. 1H NMR (d6-DMSO): δ 12.47 (s, 1H), 10.47 (s, 1H), 9.23 (t, 1H, J = 5.9 Hz), 8.13 (s, 1H), 8.05 (s,1H), 7.71 (d, 2H, J = 6.8 Hz), 7.51-7.63 (m, 4H), 7.35-7.40 (m, 2H), 7.12-7.18 (m, 2H), 4.46 (d,2H, J =5.7 Hz). HRMS calculated for C24H18N4O2F 413.1414 (M+H), found 413.1394.

Example 104: 6-Oxo-2-phenvl-/V-(2.3.5-trifluorobenzvl)-5.6-dihvdro-1H-f1.21diazepinof4,5.6- cdlindole-8-carboxamide

HN-N

Préparation of example 104 from the title compound of Example 49 (0.101 g, 0.294 mmol), 2,3,5-trifluorobenzylamine (0.0947 g, 0.588 mmol), triethylamine (0.082 mL, 0.588 mmol), and O-(7-azabenzotriazol-1-yl)-/V,N,/V;/V-tetramethyluronium hexafluorophosphate (0.224 g, 0.588 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.006 g) as a yellow powder in 4.5% yield. 1H NMR (dg-DMSO): δ 12.50 (s, 1H), 10.49 (s, 1H), 9.27 (t, 1H, J = 5.9 Hz), 8.13 (s, 1H), 8.05 (s,1H), 7.71 (d, 2H, J = 6.8 Hz), 7.52-7.62 (m, 4H), 7.40-7.48 (m, 1H), 7.05-7.08 (m, 1H), 4.56 (d,2H, J =4.9 Hz). HRMS calculated for C24H16N4O2F3 449.1225 (M+H), found 449.1209. 013017

Example_105:_/V-i3.5-Bis(trifluoromethvhbenzvn-6-oxo-2-phenvl-5,6-dihvdro-1H- f 1.21diazepinof4,5,6-ccflindole-8-carboxamide 144

Préparation of example 105 from the title compound of Example 49 (0.101 g, 0.294 mmol), 3,5-5 bis(trifluoromethyl)benzylamine (0.143 g, 0.588 mmol), triethylamine (0.082 ml_, 0.588 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafiuorophosphate (0.224 g, 0.588mmol) in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic. acid), also in an analogous manner, afforded the titlecompound (0.004 g) as a yellow powder in 2.6% yield. 10 ’H NMR (d6-DMSO): § 12.50 (s, 1H), 10.50 (s, 1K), 9.37 (t, 1H, J = 5.9 Hz), 8.14 (s, 1H), 8.05 (m,3H), 8.00 (s, 1H), 7.71 (d, 2H, J = 8.3 Hz), 7.52-7.62 (m, 4H), 4.67 (d, 2H, J = 5.7 Hz). HRMS calculated for C26H17N4O2F6 531.1256 (M+H), found 531.1272.

Example_106:_Z\/-f4-Fluoro-3-ftrifluoromethvhbenzvn-6-oxo-2-phenvl-5.6-dihvdro-1H- H.21diazeDinof4.5.6-cd1indole-8-carboxamide

Préparation of example 106 from the title compound of Example 49 (0.105 g, 0.306 mmol), 4-fluoro-3- (trifluoromethyl)benzylamine (0.118 g, 0.612 mmol), triethylamine (0.085 mL, 0.612mmol), and 0-(7-azabenzotriazol-1-yl)-/V,W,A/',W’-tetramethyluronium hexafiuorophosphate (0.233g, 0.612 mmol) in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC 20 (20-100% CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the title compound (0.0205 g) as a yellow powder in 14% yield. 1H NM,R (d6-DMSO): δ 12.49 (s, 1H), 10.48 (s, 1H), 9.30 (t, 1H, J = 5.9 Hz), 8.13 (s, 1H), 8.05 (m,3H), 7.69-7.75 (m, 4H), 7.45:7.63 (m, 5H), 4.53 (d, 2H, J = 5.7 Hz). HRMS calculated for C2SH17N4O2F4 481.1287 (M+H), found 481.1291. 013017 145

Example 107: A/-f(1-Hvdroxv-5.7-dimethvl-1,2,3.4-tetrahvdronaphthalen-1-vl)methyn-6-oxo-2- phenvl-5,6-dihvdro-1 H-ï 1.2)diazepinof4,5.6-cd)indole-8-carboxamide

HN—N

Préparation of example 107 from the title compound of Example 49 (0.104 g, 0.303 mmol), 1-5 (aminomethyl)-5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.124 g, 0.606 mmol),triethylamine (0.084 mL, 0.606 mmol), and 'O-(7-azabenzotriazol-1-yl)-/V,W,W’,W-tetramethyluronium hexafluorophosphate (0.23 g, 0.606 mmol) in DMSO (2 mL) was carried outanalogously to Example 76. Préparative HPLC (20-100% CH3CN/H2O containing 0.1%trifluoroacetic acid) also in an analogous manner afforded the title compound (0.0145 g) as a 10 yellow powder in 9.7% yield. 1H NMR (de-DMSO): δ 12.47 (s, 1 H), 10.48 (s, 1H), 8.48-8.52 (m, 1 H), 8.10 (s, 1H), 8.03 (s, 1H),7.70-7.73 (m, 2H), 7.52-7.62 (m, 4H), 7.25 (s, 1 H), 6.86 (s, 1 H), 3.66-3.73 (m, 2H), 2.55-2.63 (m,2H), 2.22 (s, 3H), 2.14 (s, 3H), 1.81-1.98 (m, 4H). HRMS calculated for C30H29N4O3 493.2240 (M+H), found 493.2252. 15 Example 108: N-l( 1 R)-1 -( 1 -Naphthvl)ethvll-6-oxo-2-phenvl-5,6-dihvdro-1 H-ï 1.21diazepinof4.5.6- cdlindole-8-carboxamide

HN-N

Préparation of example 108 from the title compound of Example 49 (0.105 g, 0.306 mmol), 1-(1-naphthyl)ethylamine (0.105 g, 0.612 mmol), triethylamine (0.085 mL, 0.612 mmol), and O-(7- 20 azabenzotriazol-1-yl)-W,W,W’,W’-tetramethyluronium hexafluorophosphate (0.233 g, 0.612 mmol) inDMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing Q.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0161 g) as a yellow powder in 12% yield. 1H NMR (d6-DMSO): δ 12.44 (s, 1H), 10.46 (s, 1H), 9.14 (d, 1H, J = 7.9 Hz), 8.17 (s, 1H), 8.05 (s, 25 1 H), 7.87-7.90 (m, 4H), 7.69-7.72 (m, 2H), 7.46-7.63 (m, 7H), 5.34-5.140 (m, 1 H), 1.61 (d, 3H, J = 6.8 Hz). HRMS calculated for C29H23N4O2 459.1821 (M+H), found 459.1795. 013017

Example 109: Diethvl 2-i[(6-oxo-2-phenyl-5,6-dihydro-1/-/-i1,2idiazepinof4.5,6-ccflindol-8- vhcarbonvllaminolmalonate 146

Préparation of example 109 from the title compound of Example 49 (0.106 g, 0.309 mmol), diethyl5 2-aminomalonate hydrochloride (0.131 g, 0.618 mmol), triethylamine (0.129 mL, 0.926 mmol),and O-(7-azabenzotriazol:1-yl)-/V,A/,/V’,/V-tetramethyluronium hexafluorophosphate (0.235 g, 0.618 mmol) in DMSO (2 mL) was carried out analogously to Example 76. Préparative HPLC (20-100% CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, affordedthe title compound (0.0064 g) as a yellow powder in 4.5% yield. 10 1H NMR (ds-DMSO): δ 12.53 (s, 1 H), 10.50 (s, 1H), 9.55 (t, 1K, J = 7.6 Hz), 8.14 (s, 1H), 8.07 (s,1H), 7.71-7.73 (m, 2H), 7.52-7.62 (m, 4H), 5.29-5.32 (m, 2H), 4.15-4.25 (m, 4H), 1.23 (t, 6H, J =7.2 Hz). HRMS caiculated for C24H23N4O6 463.1618 (M+H), found 463.1606.

Example_110:_Λ/-Κ1 R)-2-Hvdroxv-1-phenvlethvll-6-oxo-2-phenvl-5,6-dihvdro-1 H- 15 11.21diazepinof4,5.6-cdlindole-8-carboxamide

Préparation of example 110 from the title compound of Example 49 (0.17 g, 0.5 mmol), (2R)-2-amino-2-phenylethanol (0.0822 g, 0.6 mmol), triethylamine (0.14 mL, 1 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/\/,/\/’,/V-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) in 20 DMSO (8 mL) was carried out analogously to Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the titlecompound (0.0351 g) in 17% yield. 1H NMR (de-DMSO): δ 12.45 (s, 1H), 1047 (s, 1H), 8.92 (d, 1H, J =7.9 Hz), 8.17 (s, 1H), 8.04 (s,1H), 7.75-7.65 (m, 2H), 7.65-7.50 (m, 4H), 7.45-7.37 (m, 2H), 7.37-7.27 (m, 2H), 7.27-7.15 (m, 25 1H), 5.18-5.01 (m, 1H), 3.83-3.60 (m, 2H). LCMS: (M+H+) 425.1

Anal. Calcd. for C25H20N4O3 · 0.2 trifluoroacetic acid » 1.68 H2O.· C, 63.88; H, 4.97; N, 11.73.Found: C, 63.86; H, 4.97; N, 11.66. 013017 147

ExampLe—HL—L1.R.2R)-2-Phenvl-cvclopropanecarboxvlic acid f2-(3-cvclobütvlaminomethyl- phenvl)-6-oxo-5.6-dihvdro-1H-f1.2ldiazepino[4.5.6-ccüindol-8-vll-amide (hvdrochloric saitt

Intermediate 85 (a)Example 85 1. POCI3. DMF, CH2CI2 2. NH2NH2.H2O.AcOHMeOH, reflux, 81%

40%

5 Step 1. Préparation of (1R,2R)- 2-{3-[(iert-Butoxycarbonyl-cyclobutyl-amino)-methyl]-phenyl}-6-[(2-pbenyl-cyclopropanecarbonyl)-amino]-1H-indole-4-carboxy,ic acid methylester 111(a)

To a suspension of Intermediate 85(a) of Example 85 (0.260 g. 0.6 mmol) in dichloromethane (6.0mL. 0.1 M) was added 2,4,6-Collidine (0.312 mL, 2.4 mmol) followed by (CH3SO2)2O (0.123 g, 0.7 10 mmol). After stirring for 1 hour, cyclobutylamine (0.252 mL, 3.0 mmol) was added, and thereaction mixture stirred for 24 hours at 22 °C. The volatiles were removed in vacuo anddichloromethane (6.0 mL), trïethylamine (3 mmol) and di-tezï-butyl dicarbonate (1.2 mmol) wereadded. The mixture was stirred at 22 °C for 12 hours and volatiles were removed in vacuo. Silicagel chromatography provided Intermediate 111(a) (0.14 g, 0.24 mmol) in 40% yield. 15 1H-NMR (de-DMSO): δ 11.82 (s, 1 H), 10.42 (s, 1H), 8.27 (s, 1H), 7.89 (d, 1H, J* 1.6 Hz), 7.72 (d,1H, J= 8.1 Hz), 7.67 (s, 1H), 7.44 (dd, 1H, J = 7.7, 7.6 Hz), 7.36-7.08 (m,.7H), 4.51 (s, 2H), 3.91(s, 3H), 2.45-2.37 (m, 1H), 2.14-1.95 (m, 5H), 1.62-1.22 (m, 14H). 013017 148

Step 2. Préparation of (1R,2R)-Cyclobutyl-(3-{6-oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-2-yl}-benzyl)-carbamic acid ieri-butylester 111 (b)

In a manner analogous to steps 4 and 5 of Example 3, Intermediate 111(a) (0.13 g, 0.22 mmol)5 was formylated and cyclized. After silica gel chromatography, Intermediate 111 (b) (0.107 g, 0.18 mmol) was obtained as a yellow powder in 81 % yield. ’H-NMR (d6-DMSO): δ 12.09 (s, 1H), 10.43 (s, 1H), 10.37 (s, 1H), 8.16 (d, 1H, J = 1.2 Hz), 7.63(d, 1H, J = 1.4 Hz), 7.55-7.42 (m, 4H), 7.35-7.16 (m, 6H), 4.53 (s, 2H), 2.45-2.37 (m, 1H), 2.14-1.95 (m, 5H), 1.60-1.23 (m, 14H). 10 LCMS: (M-H+) 602.2.

Step 3. Préparation of Title Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-{3-cyclobutylaniinoniethyJ-phenyl)-6-oxo-5,6-diliydro-1W-[1,2]diazepino[4,5,6-cflflindol-8-yf|-amide (hydrochloric sait)

Préparation from Intermediate 111 (b) (0.105 g, 0.17 mmol) and 4M HCl in dioxane (1.7 mL) was15 carried out analogously to Example 91. Isolation, also in an analogous manner, included a furthertrituration with CH2CI2/diethyl ether and afforded the title compound (0.09 g, 0.17 mmol) as an orange/yellow powder in 96% yield. 1H-NMR (de-DMSO): δ 12.20 (s, 1H), 10.49 (s, 1H), 10.43 (s, 1H), 9.32 (b, 1H), 8.18 (d, 1H, J =1.4 Hz), 7.83 (s, 1H), 7.75-7.58 (m, 5H), 7.35-7.15 (m, 5H), 4.13 (s, 2H), 3.80-3.50 (buried m, 1H), 20 2.45-2.35 (m, 1H), 2.28-2.08 (m, 5H), 1.88-1.75 (m, 2H), 1.55-1.47 (m, 1H), 1.42-1.34 (m, 1H). LCMS: (M+H+) 504.2. HRMS. (M+H+) calcd for C31H3oN502, 504.2400, found 504.2378.

Examole 112: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid r6-oxo-2-(3-pyrroiidin-1-ylmethvl- 25 phenvD-5,6-dihvdro-1 H-11.2ldiazepinoi4,5,6-cdlindol-8-vll-amide (hydrochloric sait) 013017 149 OMe

1. (CH3SO2)2O

CH2CI2i 9%

Step 1. Préparation of (1R,2R) 6-[(2-Phenyl-cyclopropanecarbonyl)~amino]-2-(3-pyrrolidin-1-ylmethyl-phenyl)-1 H-indole-4-carboxylic acid methyl ester 112(a) 5 To a suspension of Intermediate 85(a) of Example 85 (0.260 g, 0.6 mmol) in dichloromethane (6.0mL, 0.1 M) was added 2,4,6-Collidine (0.312 mL, 2.4 mmol) followed by (CH3SO2)2O (0.123 g, 0.7mmol). After stirring for 1 hour, pyrrolidine (0.252 mL, 3.0 mmol) was added and the reactionmixture stirred for 24 hours at 22 °C. Volatiles were removed in vacuo, and the crude Intermediate112(a) was carried on directly to the next step. 10 Step 2. Préparation of Titie Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1 -ylmethyl-phenyl)-5,6-dihydro-1 /7-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide (hydrochloric sait)

In a manner analogous to steps 4 and 5 of Example 3, Intermediate 112(a) (0.42g, 0.85 mmol)was formylated and cyclized. Silica gel chromatography (90:10:0 to 70:20:10 CH2CI2/2.0 M 15 ammonia in isopropyl alcohol/methyl alcohol) and conversion to the HCl sait (4M HCl in dioxane)afforded the titie compound (0.04 g, 0.18 mmol) as a yellow-orange powder in 9% yield. 1H-NMR (d6-DMSO): δ 12.20 (s, 1H), 10.55 (s, 1H), 10.49 (s, 1H), 10.43 (b, 1H), 8.19 (d, 1H, J =1.3 Hz), 8.13 (s, 1H), 7.76-7.62 (m, 5H), 7.34-7.16 (m, 5H), 4.45 (d, 2H, J = 5.5 Hz), 3.45-3.35 (m,2H), 3.19-3.07 (m, 2H), 2.45-2.35 (m, 1H), 2.14-1.85 (m, 5H), 1.55-1.47 (m, 1H), 1.42-1.34 (m, 20 1H). LCMS: (M+hT) 504.2. HRMS: (M+H+) calcd for C31H30N5O2, 504.2400, found 504.2404.

Example 113: A/-(6-Oxo-2-phenvl-5.6-dihvdro-1 rt-f 1.2ldiazepinof4.5,6-cc/lindol-8-vl)-( 1,2-trans)-2- f6-ftrifluoromethvl)pyridin-3-vllcvclopropanecarboxamide trifluoroacetate 013017 150

Step 1. Préparation of 3-(6-Trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester 113(a)

To a solution of triethyl phosphite in anhydrous tetrahydrofuran (25 mL) cooled to 0 °C was addeda 60% suspension of sodium hydride in minerai oil (472 mg, 19.7 mmol) in small portions. Thismixture was allowed to stir for 30 min at the same low température at which point the cooling bathwas removed, and the mixture wâs allowed to warm to room température over 60 min. Themixture was cooled again to 0 °C and a solution of 6-trifluoromethyl-3-pyridine carboxaldehyde inanhydrous tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was allowed towarm slowly to room température ovemight. After 19 hours, the reaction mixture was quenchedwith water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic fractionswere dried over anhydrous magnésium sulfate and concentrated to a pale green oil. Purificationwas carried out using flash silica gel chromatography eluting with 5:95 then 1:9 ethylacetate:hexane. Pure fractions were combined and concentrated to afford Intermediate 113(a)(1.68 g, 6.85 mmol) as a white solid in 42% yield.

Step 2. Préparation of (1,2-fra/7s)-2-(6-Trifluoromethyl-pyridin-3-yl)-cyclopropanecarboxylicacid 113(b)

Trimethylsulfoxonium iodide (574 mg, 2.61 mmol) was added to 60% NaH in minerai oil (63 mg,2.61 mmol), and the flask was purged with nitrogen. Methyl sulfoxide (10 mL) was added slowlyover 20 minutes until évolution of hydrogen ceased. To this milky solution was added Intermediate113(a) (493 mg, 2.01 mmol) in methyl sulfoxide (15 mL) dropwise. The solution was allowed to stirat room température ovemight. After 26 hours the excess NaH was carefully quenched with water(100 mL). Ethyl ether (100 mL) was added and the layers separated. The aqueous layer wasextracted with fresh ethyl ether (3 x 50 mL). The combined ethereal layers were washed withbrine, dried over anhydrous magnésium sulfate and concentrated in vacuo. Flash silica gel 0130^7 151 chromatography of the crude residue eluting with 1:9 then 1:4 ethyl acetate:hexane gave twopure fractions that upon combining and concentrating under reduced pressure yieldedIntermediate 113(b) (275 mg, 1.06 mmol) as white feathers in 53% yield.

Step 3. Préparation of (1,2-frans)-2-[6-(Trifluoromethyl)pyridin-3-yl]cyclopropanecarboxyIicacid113(c)

To a solution of Intermediate 113(b) (275 mg, 1.06 mmol) in a 1:1 mixture oftetrahydrofuran.water (4 mL) was added lithium hydroxide monohydrate (133 mg, 3.18 mmol).The semi-suspension was allowed to stir at room température over 2 days. The reaction mixturewas acidified with 2M aqueous hydrochloric acid (c.a. 2 mL). The reaction mixture was thenconcentrated and lyophilized to obtain Intermediate 113(c) as a white powder containing lithiumchioride which was carried on directly without further purification.

Step 4. Préparation of Title Compound: W-fB-Oxo^-phenyl-S^-dihydro-IH- [1.2]diazepino[4,5,6-ccQindol-8-yl)-2-[6-(trifluoromethyl)pyridin-3-yljcyclopropanecarboxamide trifluoroacetate

To a solution of Intermediate 113(c) (85 mg, 0.368 mmol) in methyl sulfoxide (2 mL) was addedtriethylamine (0.056 mL, 0.405 mmol) and 0-(7-azabenzotriazol-1-yl)-/V,/V,A/’,/V-tetramethyluronium hexafluorophosphate (154 mg, 0.405 mmol). After c.a. 10 min, the titlecompound of Example 7 (0.102 g, 0.368 mmol) was added. The réaction was capped and stirredovernight at room température. The mixture was subjected to préparative HPLC (20-100%acetonitrile/water containing 0.1% trifluoroacetic acid). The pure fractions were combined andlyophilized to afford the title compound (27 mg, 0.045 mmol) as an orange powder in 12% yield.1H-NMR (d6-DMSO): δ 12.11 (b, 1H), 10.50 (b, 1H), 10.39 (b, 1H), 8.71 (b, 1 H), 8.15 (b, 2H), 7.90-7.80 (m, 2H), 7.70-7.45 (m, 6H), 2.65-2.55 (m, 1H), 2.27-2.18 (m, 1H), 1.67-1.51 (m, 2H). LCMS: (M+H4) 490.1.

Example 114: (2R)-2-Amino-/V-(6-oxo-2-phenvl-5.6-dihvdro-1H-(1.21diazepinor4.5,6-ccflindol-8-vh- 2-phenvl-acetamide (hydrochloric sait)

Préparation of example 114 from the impure title compound of Example 117 (90 mg, 0.18 mmol)and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, afforded the title compound (65 mg, 0.10 mmol) as a yellow powder in 71%yield over two steps (including Example 117). 01301 7 152 1Η NMR (d6-DMSO): δ 12.26 (s, 1 Η, exchanges), 11.08 (s, 1Η, exchanges), 10.42 (s, 1H,exchanges), 8.86 (br s, 3H, exchanges), 8.07 (s, 1H), 7.72-7.63 (m, 5H), 7.62-7.41 (m, 7H), 5.22(m, 1H). LCMS: (M+H+) 410.1, (M+Na+) 432.0. 5 Anal. Calcd. for C24H,eN5O2'5.6 HCl · 0.2 dietbyl ether: C, 47.40; H, 4.27; N, 11.14.

Found: C,^47.64; H, 4.21; N, 10.91.

Example 115: (2R)-2-Amino-A/-(6-oxo-2-phenvl-5.6-dihvdro-1H-f1.21diazeDinof4.5.6-ccflindol-8-vn- 3-phenvl-propionamide (hvdrochloric sait)

10 Préparation of example 115 from the title compound of Example 118 (71 mg, 0.136 mmol) and4M HCl in dioxane (20 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, afforded the title compound (66 mg, 0.12 mmol) as a yellow powder in 87%yield over two steps (from Example 118). 1H NMR (d6-DMSO): δ 12.20 (s, 1H, exchanges), 10.66 (s, 1H, exchanges), 10.44 (s, 1H, 15 exchanges), 8.39 (brs, 3H, exchanges), 8.05 (s, 1H), 7.73-7.46 (m, 7H), 7.39-7.22 (m, 5H), 4.19(m, 1H), 3.21-3.06 (m, 2H, partially obscured). LCMS. (M+H+) 424.1.

Anal. Calcd. for C2SH21N5O2 · 2.8 HCl ' 0.1 diethyl ether · 0.2 dioxane: C, 57.15; H, 4.83; N, 12.72.Found: C, 57.33; H, 5.01; N, 12.56. 20 Example 116: 1-Amino-cyclohexanecarboxvlic acid (6-oxo-2-phenyl-5.6-dihvdro-1/V- |1.21diazepinof4,5,6-cd1indol-8-vl)-amide (hvdrochloric sait)

Préparation of exampie 116 from the title compound of Example 119 (311 mg, 0.062 mmol) and4M HCl in dioxane (5 mL) was carried out analogously to Example 91. Isolation, also in an 25 analogous manner, included a further trituration with CH2CI2/hexane and afforded the title compound (29 mg, 0.053 mmol) as an orange/yellow powder in 85% yield. 1H NMR (d6-DMSO): δ 12.29 (s, 1H, exchanges), 10.44 (s, 1H, exchanges), 10.28 (s, 1H, exchanges), 8.36 (br s, 3H, exchanges), 8.11 (s, 1H), 7.81 (s, 1H), 7.74-7.46 (m, 6H), 2.37-2.14 (m, 2H), 1.96-1.35 (m,8H). 01301 153 H’ LCMS: (M+H+) 402.2, (M+Na+) 424.1.

Anal. Calcd. for C23H23N5O2'3.1 HCl ' 0.1 diethyl ether · 0.3 dioxane: C, 53.88; H, 5.42; N, 12.77.Found: C, 53.86; H, 5.60; N, 12.70.

Example 117: f(R)-f6-Oxo-2-phenvl-5.6-dihvdro-1H-ri ,21diazepinof4.5.6-ccnindol-8-vlcarbamovl)- phenvl-methyn-carbamic acid terf-butvl ester

10 15 20

Préparation of example 117 from the the title compound of Example 7 (hydrochloride) (44 mg,0.141 mmol), (R)-terf-butoxycarbonylamino-phenyl-acetic acid (42 mg, 0.169 mmol), triethylamine(0.059 mL, 0.423 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,A/,/V’/V'-tetrarnethyluroniurnhexafluorophosphate (64 mg, 0.169 mmol) in CH2CI2 (0.4 mL) and /V,/V-dimethylformamide (0.4mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1hexane:acetone), also in an analogous manner, afforded the title compound (102 mg) as a yellowpowder contaminated with an unknown impurity. The compound was an intermediate and carriedon without further purification to Example 91. ’H NMR (d6-DMSO): δ 12.12 (s, 1H), 10.41 (s, 2H), 8,12 (s, 1H), 7.69-7.48 (m, 10H), 7.42-7.27(m, 3H), 5.36 (d, 1 H, J = 8.67 Hz), 1,41 (s, 9H). LCMS: (M-H‘) 508.1, (M+H+) 510.2, (M+Na+) 532.2.

Example_118:_f(R)-1-(6-Oxo-2-phenyl-5.6-dihvdro-1H-f1.21diazepino[4.5.6-cc/lindol-8- vlcarbamovh-2-phenvl-ethvll-carbamic acid terf-butvl ester

Préparation of example 118 from the title compound of Example 7 (hydrochloride) (43 mg, 0.138mmol), (R)-ferf-butoxycarbonylamino-3-phenyl-propionic acid (44 mg, 0.166 mmol), triethylamine(0.058 mL, 0.414 mmol), and O-(7-azabenzotriazol-1-yl)-A/,/V,/V’,W-tetramethyluroniumhexafluorophosphate (63 mg, 0.166 mmol) in CH2CI2 (0.4 mL) and W,/V-dimethylformamide (0.4mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1hexane:acetone), also in an analogous manner, afforded the title compound (80 mg) as a yellowpowder contaminated with an unknown impurity. The compound was carried on without furtherpurification to Example 115. 25 013017 154 1H NMR (ds-DMSO): δ 12.12 (1 H), 10.41 (s, 1 H), 10.25 (s, 1H), 8.18 (s, 1H), 7.71-7.48 (m, 7H),7.38-7.11 (m, 6H), 4.34 (br s, 1 H), 3.02 (m, 1H), 2.87 (m, 1H, partially obscured by N,N-dimethylformamide singlet), 1.34 (s, 9H). LCMS: (M+H+) 524.2, (M+Na+) 546.2. 5 Example 119: H-i6-Oxo-2-phenyl-5.6-dihvdro-1 W1.21diazepinor4.5,6-cdlindol-8-vlcarbamov0- cvclohexvn-carbamic acid tert-butyl ester

Préparation of example 119 from the title compound of Example 7 (hydrochloride) (45 mg, 0.142mmol), Irferf-butoxycarbonylamino-cyclohexanecarboxylic acid (42 mg, 0.171 mmol), 10 triethylamine (0.059 mL, 0.426 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V’,/V-tetramethyluronium hexafluorophosphate (65 mg, 0.171 mmol) in CHZCIZ (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (38 mg, 0.076 mmol) as a yellow powder in 53% yield. 15 1H NMR (d6-DMSO): δ 12.08 (s, 1 H), 10.37 (s, 1 H), 9.59 (s, 1H), 8.14 (s, 1H), 7.70-7.48 (m, 8H),2.03-1.92 (m, 2H), 1.81-1.71 (m, 2H), 1.47 (m, 5H), 1.40-1.31 (m, 10H). LCMS: (M+H+) 502.1, (M+Na+) 524.1.

Example 120: (3E)-4-Phenvl-but-3-enoic acid (6-oxo-2-phenvl-5,6-dihvdro-1H- f1.21diazepinof4.5,6-cd1indol-8-vl)-amide

Préparation of example 120 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141mmol), (E)-4-phenyl-but-3-enoic acid (27 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol),and 0-(7-azabenzotriazol-1-yl)-/V,A/,ZV'W'-tetramethyluronium hexafluorophosphate (64 mg, 0.169mmol) in CHZCI2 (0.4 mL) and /V,/V-dimethyiformamide (0.4 mL) was carried out analogously to 25 Example 11. When the reaction was judged complété, the mixture was filtered to collect thesolids which were then washed with methanol. After drying under vacuum, the title compound (41mg, 0.0.095 mmol) was obtained as a yellow powder in 68% yield. 1H NMR (d6-DMSO): δ 12.10, (s, 1H, exchanges), 10.38 (s, 1H, exchanges), 10.22 (s, 1H,exchanges), 8.21 (s, 1H), 7.77-7.63 (m, 3H), 7.60-7.53 (m, 2H), 7.53-7.42 (m, 4H), 7.38-7.30 (m, 30 2H), 7.24(m, 1H), 6.57 (d, 1H, J= 16.01 Hz), 6.45 (m, .1H). 013017 155 1H NMR (d6-DMSO/DCI): δ 8.20 (s, 1 H), 7.75 (s, 1 H), 7.71-7.65 (m, 2H), 7.60-7.47 (m, 4H), 7.43-7.37 (m, 2H), 7.38-7.29 (m, 2H), 7.22 (m, 1H), 6.55 (d, 1H, J= 16.23 Hz), 6.44 (m, 1H), 3.33 (d,2H, J =9.09 Hz). LCMS: (M+H+) 421.1, (M+Na+) 443.1. 5 Anal. Calcd. for C26H20N4O2'0.1 H2O · 0.1 /V,/V-dimethylformamide: C, 73.53; H, 4.90; N, 13.37.Found: C, 73.26; H, 4.50; N, 13.61.

Example 121: 2-lndan-2-vl-/\Z-f6-oxo-2-phenvl-5.6-dihvdro-1H-f1.2ldiazepinof4.5.6-cd1indol-8-vl)- acetamide

10 Préparation of example 121 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131mmol), indan-2-yl-acetic acid (28 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,A/',/V-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol)in CH2CI2 (0.4 mL) and /V,A/-dimethylformamide (0.4 mL) was carried out analogously to Example11. When the reaction was judged complété, the mixture was filtered to collect the solids, which 15 were then washed with methanol. After drying under vacuum, the title compound (45 mg, 0.101mmol) was obtained as a yellow powder in 77% yield. 1H NMR (d6-DMSO): δ 12.08, (s, 1H, exchanges), 10.37 (s, 1H, exchanges), 10.11 (s, 1H,exchanges), 8.20 (s, 1H), 7.70.-7.45 (m, 7H), 7.26-7.18 (m, 2H), 7.16-7.08 (m, 2H), 3.07 (dd, 2H,J = 7.72, 15.83 Hz), 2.87 (m, 1 H), 2.65 (dd, 2H, J = 6.59, 15.26 Hz). 20 LCMS: (M+H+) 435.2, (M+Na+) 457.1.

Anal. Calcd. for C^Hal^A 0.5 H2O: C, 73.12; H, 5.23; N, 12.63.

Found: C, 72.84; H, 4.99; N, 12.99.

Example 122: /V-(6-Oxo-2-phenvl-5.6-dihvdro-1H-i1.21diazepinol4.5.6-cd1indoi-8-vl,)-2-(toluene-4- sulfonvlaminol-benzamide

Préparation of example 122 from the title compound of Example 7 (100 mg, 0.362 mmol), 2- (toluene-4-sulfonylamino)-benzoic acid (158 mg, 0.542 mmol), triethylamine (0.201 mL, 1.446 mmol), and O-(7-azabenzotnazol-1-yl)-/V,/V,A/',/V-tetramethyluronium hexafluorophosphate (206 mg, 0.542 mmol) in /V,/V-dimethylformamide (4.0 mL) was carried out analogously to Example 11. 30 When the reaction was judged complété, Λ/,/V-dimethylformamide was evaporated and methanol 013017 156 was added. The mixture was filtered and the solids collected and washed with methanol,dichloromethane and diethyl ether. After drying under vacuum, the title compound (121 mg, 0.220mmol) was obtained as a yellow powder in 61 % yield. 1H NMR (ds-DMSO): δ 12.19 (s, 1 H), 10.63 (s, 1 H), 10.45 (s, 1H), 10.42 (s, 1H), 8.12 (s, 1H), 7.85-7.78 (m, 2H), 7.74-7.67 (m, 2H), 7.64-7.56 (m, 4H), 7.56-7.42 (m, 4H), 7.29-7.20 (m, 3H), 2.27 (s, 3H). LCMS: (M+l-f) 550.1; (M-H)' 548.2. HRMS: (M+H+) calcd for C30H24N5O4S, 550.1549, found 550.1551.

Anal. Calcd. for C3oH23N504S 0.5 H2O: C, 64.50; H, 4.33; N, 12.54. 10 Found: C, 64.51; H, 4.20; N, 12.71.

Example 123: 6-Oxo-2-phenvl-5,6-dihvdro-1H-H,21diazepinoi4,5.6-cdlindole-8-carboxvlic acid phenethvi-amide

HN—N 15 Préparation of example 123 from the title compound of Example 49 (0.17 g, 0.5 mmol),phenethylamine (73 mg, 0.6 mmol), triethylamine (100 mg, 1.0 mmol), and O-(7-azabenzotriazol-1-yl)-/V,W,/V’,/V-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) in DMSO (8 mL) wascarried out analogously to the préparation of Example 76. Préparative HPLC (20-100%CH3CN/H2O containing 0.1% trifluoroacetic acid), also in an analogous manner, afforded the title 20 compound (0.021 g) as a yellow powder in 9% yield. 1H NMR (de-DMSO): δ 12.49 (s, 1 H), 10.49 (s, 1H), 8.77 (t, 1H, H=5.5 Hz), 8.07 (s, 1H), 8.00 (s,1 H), 7.10-7.80 (m, 11 H), 3.48 (m, 2H), 2.86 (t, 2H, J = 7.5 Hz). LCMS (M++1):409.1

Example 124: (1.2-fra/7s)-2-(4-Fluoro-phenvl)-cvclopropanecarboxvlic acid (6-oxo-2-phenyl-5.6- 25 dihvdro-1 H-11.21diazepinof4.5,6-cdlindol-8-vl)-amide

HN—N

HN—N HATU, Et3N, DMSO, 52% *-

013017 157

Préparation of example 124 was carried out analogously to the préparation of Example 113except that (1,2-frans)-2-(4’-fluorophenyl)-cyclopropanecarboxylic acid was used instead of (1,2-frans)-2-(6-trifluoromethyl-pyridin-3-yl)-cyclôpropanecarboxylic acid in step 4. (1,2-frans)-2-(4’-Fluorophenyl)-cyclopropanecarboxylic acid was prepared using procedures similar to those 5 described in steps 1-3 of Example 113 except that 4-fluoro-benzaldehyde was used instead of 6-trifluoromethyl-3-pyridine carboxaldehyde. Final HPLC purification, also analogous to Example113, afforded the title compound (100 mg, 0.228 mmol) as a yellow powder in 62% yield. 1H-NMR (de-DMSO): δ 12.12 (b, 1H), 10.46 (b, 1H), 10.41 (b, 1H), 8.18 (b, 1H), 7.70-7.45 (m, 7H),7.30-7.10 (m, 4H), 2.65-2.55 (m, 1H), 2.27-2.18 (m, 1H), 1.67-1.51 (m, 2H). 10 HRMS: C2iH2iN5O2· H: 439.1570. Found: 439.1584.

Example 125: i1,2-frans)-2-Pvridin-3-vl-cvclopropanecarboxvlic acid (6-oxo-2-phenvl-5.6-dihvdro- 1H-f1.21diazePinoi4.5.6-cdlindol-8-yn-amide fhvdrochloric sait)

HN-N

HATU, Et3N, DMSO, 100%---► (a)

CIH.N

HN-N

15 Préparation of example 125 was carried out analogously to the préparation of Example 113except that (1,2-frans)-2-pyridin-3'-yl-cyclopropanecarboxylic acid was used instead of (1,2-frazjs)-2-(6-trifluoromethyi-pyridin-3-yl)-cyclopropanecarboxylic acid in step 4. (1,2-frans)-2-Pyridin-3’-yl-cyclopropanecarboxylic acid was prepared using procedures similar to those described in steps 1-3 of Example 113 except that pyridine-3-carbaldehyde was used instead of 6-trifluoromethyl-3- 20 pyridine carboxaldehyde. Final HPLC purification, also analogous to Example 113, afforded thetitle compound (230 mg, 0.381 mmol) as an orange fluffy solid in quantitative yield. 1H-NMR (de-DMSO): δ 12.15 (s, 1H), 10.58 (s, 1H), 10.38 (s, 1H), 8.81 (s, 1H), 8.15 (b, 2H), 7.82-7.45 (m, 9H), 2.35-2.25 (m, 1H), 1.70-1.51 (m, 1H), 1.35-1.10 (m, 1H), 0.90-0.65 (m, 1H). LCMS: (M+H+) 422.1. 25 Example 126: (t.2-frans)-2-f3-Methoxv-phenvl)-cvclopropanecarboxvlic acid (6-oxo-2-phenvl-5.6- dihvdro-1H-H.2ldiazepinoi4,5.6-cd1indol-8-vl)-amide

HN-N

HATU, Et3N, DMSO, 74%->. (a) <?

MeO-

MeO

HN-N

013017 158

Préparation of example 126 was carried out analogously to the préparation of Example 113except that (1,2-frans)-2-(3’-methoxyphenyl)-cyclopropanecarboxylic add was used instead of(1,2-fra/7s)-2-(6-trifluoromethyl-pyridin-3-yl)-cyclopropanecarboxylic acid in step 4. (1,2-trans)-2-(3'-Methoxyphenyl)-cyclopropanecarboxylic acid was prepared using procedures similar to those 5 described in Steps 1-3 of Example 113 except that 3-methoxy-benzaldehyde was used instead of6-trifluoromethyl-3-pyridine carboxaldehyde. Final HPLC purification, also analogous to Example113, afforded the title compound (132 mg, 0.293 mmol) as a pale orange solid in 74% yield.1H-NMR (d6-DMSO): δ 12.09 (s, 1 H), 10.43 (s, 1H), 10.38 (s, 1H), 8.15 (s, 1 H), 7.70-7.40 (m, 7H),7.25-7.15 (m, 1 H), 6.77 (b, 3H), 3.74 (s, 3H), 2.40-2.30 (m, 1H), 2.12-2.05 (m, 1 H), 1.55-1.47 (m, 10 1 H), 1.42-1.33 (m, 1 H). LCMS: (M+H+) 451.1.

Example 127: (R)-2-Amino-2-cyclohexvl-(6-oxo-5.6-dihvdro-1-f1,21diazepinoi4,5.6-ctï1indol-8-vh- acetamide (hvdrochloric sait) RCO2H HATU / HN-N HN-NOss/ < °ss/ 4N HCl (Dioxane) Title Compound -*- ! I ïï il I 7 of Example 2 Et3N, DMF X ''N CH2CI2i 92% ΝΗΒοί1 H H-CI RH2 H h 127(a) 15

Step 1. Préparation of [(R)-Cyclohexyl-(6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-y!carbamoyl)-methyl]-carbamic acid tert-butyi ester 127(a)

Préparation of Intermediate 127(a) from the title compound of Example 2 (105 mg, 0.445 mmol),(R)-tert-butoxycarbonylamino-cyclohexyi-acetic acid (172 mg, 0.668 mmol), triethylamine (0.248 20 mL, 1.782 mmol), and 0-(7-azabenzotriazol-1-yl)-A/,A/,W’/\/-tetramethyluroniumhexafluorophosphate (254 mg, 0.668 mmol) in Λ/,/V-dimethylformamide (4,0 mL) was carried outanalogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:ethyl acetate), alsoin an analogous manner, afforded Intermediate 127(a) (110 mg, 0.250 mmol) as a yellow powderin 56% yield. 25 1H NMR (ds-DMSO): δ 11.71 (d, 1H, J = 2.26 Hz), 10.23 (s, 1H), 10.07 (s, 1H), 8.10 (s, 1H), 7.59(s, 1H), 7.55 (d, 1H, J = 2.45 Hz), 7.46 (s, 1H), 6.86 (d, 1H, J= 8.85 Hz), 3.92 (dd, 1H, J= 8.10,7.91 Hz), 1.77-1.46 (m, 6H), 1.37 (s, 9H), 1.24-0.93 (m, 5H). LCMS: (M+H+) 440.1, (M+Na+) 462.2; (M-H)' 438.2.

Step 2, Préparation of Title Compound: (R)-2-Amino-2-cyclohexyl-(6-oxo-5,6-dihydro-1- 30 [1,2]diazepino[4,5,6-cd|indol-8-yl)-acetamide (hydrochloric sait)

Préparation of the title compound from Intermediate 127(a) (66.1 mg, 0.150 mmol) and 4.0 M HClin dioxane (1.5 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (52.0 mg, 0.138 mmol) as a yellow powder in 92% yield. 013017 159 1H NMR (de-DMSO): δ 11.86 (s, 1H), 10.69 (s, 1H), 10.31 (s, 1H), 8.29 (br s, 3H), 8.08 (s, 1 H),7.63 (s, 1 H), 7.49 (s, 1 H), 3.80-3.69 (m, 1 H), 1.93-1.55 (m, 6H), 1.29-0.98 (m, 5H). LCMS: (M+H+) 340.3, (M+Na+) 362.3.

Example 128: 2-lndan-2-vl-(6-oxo-5.6-dihvdro-1-f1,2|diazepinof4,5.6-cd1indol-8-vl)-acetamide

10 15

Préparation of example 128 from. the title compound of Example 2 (freebase) (88.7 mg, 0.443mmol), indan-2-yl-acetic acid (117 mg, 0.665 mmol), triethylamine (0.247 mL, 1.774 mmol), andO-(7-azabenzotriazol-1-yl)-/V,W,W',W-tetramethyluronium hexafluorophosphate (253 mg, 0.665mmol) in W,W-dimethylformamide (4.0 mL) was carried out analogously to Example 11. When theréaction was judged complété, Λ/,/V-diméthylformamide was evaporated and methanol was added.The mixture was filtered to collect the solids, which were then washed with methanol,dichloromethane and diethyl ether. After drying under vacuum, the title compound (115 mg, 0.321mmol) was obtained as a yellow powder in 72% yield. 1H NMR (d6-DMSO): δ 11.71 (s, 1H), 10.23 (s, 1H), 10.05 (s, 1H), 8.15 (s, 1H), 7.58(s, 1H), 7.55(d, 1H, J = 2.26 Hz), 7.46 (s, 1H), 7.26-7.16 (m, 2H), 7.16-7.06 (m, 2H), 3.06 (dd, 2H, J = 7.54,5.54 Hz), 2.92-2.79 (m, 1H), 2.65 (dd, 2H, J = 6.59, 6.78 Hz), 2.47 (d, 2H, J = 9.80 Hz). LCMS: (M+H+) 359.1, (M+Na+) 381.0; (M-H)' 357.2.

Example 129: (1.2-fra/îs)-2-Pvridin-3-vl-cvclopropanecarboxvlic acid (6-oxo-5,6-dihvdro-1H- Π ,21diazepinor4.5.6-cdlindol-8-vl)-amide

HN—N 20

25

Préparation of example 129 from the title compound of Example 2 (freebase) (200 mg, 1.00mmol), (1,2-£rans)-2-pyridin-3'-yl-cyclopropanecarboxylic acid (see Example 125 for preparation-estimated purity c.a. 75%) (240 mg, c.a.1.10 mmol), triethylamine (0.550 mL, 3.96 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,W’N-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol)in /V,A/-dimethylformamide (8.0 mL) was carried out analogously to Example 11. Silica gelchromatography (eiuted with 100:10:1 ethyl acetate: methanol: ammonium hydroxide), also in ananaiogous manner, afforded the title compound (38 mg, 0.110 mmol) as a yellow powder in 11%yield. 1H NMR (de-DMSO): δ 11.73 (d, 1H, J = 2.26 Hz), 10.41 (s, 1H), 10.23 (s, 1H), 8.50 (d, 1H, J =1.88 Hz), 8.41 (dd, 1H, J = 3.20, 1.51 Hz), 8.11 (d, 1H, J= 1.51 Hz), 7.61-7.48 (m, 3H), 7.45 (s, 30 013017 160 1 K), 7.32 (dd, 1 H, J = 5.09, 3.20 Hz), 2.45-2.36 (m, 1H), 2.18-2.05 (m, 1H), 1.58-1.49 (m, 1H),1.49-1.36 (m, 1 H). LCMS: (M+H+) 346.1; (M-H)'344.1. HRMS: (M+H+) calcd for CwH^NsOz, 346.1304, found 346.1316. 5 Example 130: f1.2-frans)-2-(1’-Tritvl-1F/-imidazol-4’-vl)-cvclopropanecarboxylic acid (6-oxo-2-

Dhenvl-5.6-dihvdro-1H-|1,2ldiazepinoi4,5,6-cc/lindol-8-vl)-amide

Préparation of example 130 was carried out analogously to the préparation of Example 113except that (1,2-frans)-2-(r-trityl-1H-imidazol-4’-yl)-cyclopropanecarboxylic acid was used instead 10 of ( 1,2-ira/JS)-2-(6-trifluoromethyl-pyridin-3-yl)-cyclopropanecarboxylic acid in step 4.(1,2-trans)-2-(T-trityl-1H-imidazol-4’-yl)-cyclopropanecarboxyiic acid was prepared using procedures similar tothose described in steps 1-3 of Example 113 except that 1-trityl-1H-imidazole-4-carbaldehyde wasused instead of 6-trifluoromethyl-3-pyridine carboxaldehyde. Final purification consisted ofmethanol trituration. The resulting solids were isolated by filtration, washed with cold methanol, 15 and dried overnight under vacuum at room température to afford the title compound (263 mg,0.366 mmol) as a yellow powder in quantitative yield. 1H-NMR (de-DMSO): δ 12.09 (s, 1H), 10.43 (s, 1H), 10.38 (s, 1H), 8.13 (s, 1H), 7.70-7.30 (m,18H), 7.25 (s, 1H), 7.15-7.05 (m, 6H), 6.87 (s, 1H), 2.35-2.24 (m, 1H), 2.20-2.13 (m, 1H), 1.38-1.23 (m,2H). 20 LCMS: (M+H+) 653.3

Example 131: (6-Oxo-5, 6-dthvdro-1-f1.2)diazepinof4,5,6-1indol-8-vl)-3-(pvridin-2-vloxv)- benzamide

Préparation of example 131 from the title compound of Example 2 (25 mg, 0.125 mmol), 3-25 (pyridin-2-yloxy)-benzoic acid (88 mg, 0.348 mmol), Λ/,/V-diisopropylethyiamine (0.19 mL, 1.04mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (159mg, 0.42 mmol) in /V,A/-dimethylformamide (3 mL) was carried out analogously to Example 11. 013017 161

Silica gel chromatography (eluted with 2% methanol in CH2CI2), also in an analogous manner,afforded the title compound (20 mg, 0.05 mmol) as a yellow powder in 40% yield. ’H NMR (d6-Acetone): δ 7.92 (s, 1H), 7.89 (s, 1H), 7.55-7.52 (m, 4H), 7.39 (s, 1H), 7.37 (s, 1H),7.34 (m, 1H), 7.32-7.24 (m, 2H), 7.15 (m, 1H), 6.95 (m, 1 H), 6.93 (m, 1H), 6.77-6.73 (m, 5H), 6.88(m, 1H), LCMS: (M+H+) 398.1.

Example 132: M-(6-Oxo-5,6-dihvdro-1H-f1.21diazepinof4,5,6-cdlindol-8-vl)-4-thiophen-2-yl- butvramide

HN—N

Préparation of example 132 from the title compound of Example 2 (freebase) (200 mg, 1.00mmol), 4-thiophen-2-yl-butyric acid (187 mg, 1.10 mmol), triethylamine (0.550 mL, 3.96 mmol),and O-(7-azabenzotriazol-1-yl)-W,/V,/V’,/\/-tetramethyluronium hexafluorophosphate (570 mg, 1.50mmol) in /V./V-dimethylformamide (8.0 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with ethyl acetate), also in an analogous manner, afforded the titlecompound (72 mg, 0.204 mmol) as a yellow powder in 20% yield. 1H NMR (de-DMSO): δ 11.70 (d, 1H, J = 2.07 Hz), 10.22 (s, 1H), 10.03 (s, 1H), 8.13 (d, 1H, J =1.51 Hz), 7.55 (d, 1 H, J = 1.51 Hz), 7.53 (d, 1H, J = 2.45 Hz), 7.45 (s, 1H), 7.31 (dd, 1H, J = 4.33,0.94 Hz), 6.94 (dd, 1H, J = 3.39,1.70 Hz), 6.86 (d, 1H, J = 2.83 Hz), 3.84 (t, 2H, J = 7.54 Hz), 2.37(t, 2H, J = 7.35 Hz), 1.93 (tt, 2H, J = 7.54, 7,35 Hz). LCMS: (M+H+) 353.2, (M+Na*) 375.2; (M-H)' 351.2. HRMS: (M+H+) calcd for C18H17N4O2S, 353.1072, found 353.1056.

Anal. Calcd. for C18H16N4O2S: C, 61.35; H, 4.58; N, 15.90.

Found: C, 61.06; H, 4.52; N, 15.71.

Example 133: f2R)-2-Hydroxv-/V-(6-oxo-2-phenvl-5.6-dihvdro-1 H-f1.2tdiazepino[4.5.6-ccflindol-8- yl)-2-phenvlethanamide

Préparation of example 133 from the title compound of Example 7 (hydrochloride) (46 mg, 0.147 mmol), (2R)-hydroxy(phenyl)ethanoic acid (27 mg, 0.177 mmol), triethylamine (0.061 mL, 0.44 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (67 mg, 0.177 mmol) in CH2CI2 (0.4 mL) and A/,W-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 3:1:1 hexane:ethyl 013017 162 acetate:ethanol), also in an analogous manner, followed by two successive triturations (ethylacetate/diethyl ether then methanol/diethyl ether) afforded the title compound (34 mg, 0.082mmol) as a yellow powder in 56% yield. ’H NMR (d6-DMSO): δ 12.12, (s, 1H), 10.38 (s, 1H), 10.16 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.70-5 7.64 (m, 2H), 7.61-7.45 (m, 6H), 7.42-7.26 (m, 3H), 6.35 (br s, 1 H, partially exchanged), 5.13 (s, 1H). LCMS: (M-H)‘ 409.2.

Example 134: (1.2-frans)-2-Pvridin-2-vl-cvclopropanecarboxvlic acid (6-oxo-2-phenvl-5,6-dihvdro-

Preparafion of example 134 was carried out analogously to the préparation of Example 113except that (1,2-frans)-2-pyridin-2’-yl-cyclopropanecarboxylic acid was used instead of (1,2-trans)-2-(6-trifluoromethyl-pyridin-3-yl)-cyclopropanecarboxylic acid in step 4. (1,2-fra/7S)-2-Pyridin-2’-yi-cyclopropanecarboxylic acid was prepared using procedures similar to those described in steps 1- 15 3 of Example 113 except that pyridine-2-carbaldehyde was used instead of 6-trifluoromethyl-3- pyridine carbaldehyde. Final HPLC purification, also in an analogous manner but using 0.1%acetic acid instead of 0.1% TFA, afforded the title compound (107 mg, 0.254 mmol) as agreenish-yellow solid in 69% yield. 1H-NMR (d6-DMSO): δ 12.09 (s, 1 H), 10.43 (s, 1H), 10.38 (s, 1 H), 8.15 (s, 1H), 7.70-7.40 (m, 7H), 20 7.25-7.15 (m, 1 H), 6.77 (b, 3H), 3.74 (s, 3H), 2.40-2.30 (m, 1H), 2.12-2.05 (m, 1H), 1.55-1.47 (m, 1 H), 1.42-1.33 (m, 1 H). LCMS: (M+H+) 422.1.

Example 135: /1,2-frans)-2-(1/7-lmidazol-4-yl)-cyclopropanecarboxvlic acid (6-oxo-2-phenvl-5.6- dihvdro-1H-f1,21diazepinof4.5,6-cdlindol-8-vh-amide (acetic acid sait)

Préparation of example 135 was carried out by suspending the title compound of Example 130(260 mg, 0.398 mmol) in anhydrous dichloromethane (5 mL) and adding anhydrous trifluoroacetic 0130Π 163 acid (5 mL) at room température. After 30 minutes, the mixture was concentrated and subjectedto préparative HPLC, in a manner analogous to Example 134, to afford the title compound (72 mg,0.175 mmol) as a fiuffy yeilow solid in 44% yield. 1H-NMR (d6-DMSO): δ 12.09 (s, 1H), 10.43 (s, 1 H), 10.37 (s, 1H), 8.15 (s, 1 H), 7.97 (b, 1H), 7.70-5 7.45 (m, 7H), 7.13 (b, 1 H), 2.40-2.30 (m, 1H), 2.12-2.04 (m, 1H), 1.45-1.33 (m, 2H). LCMS: (M+H+) 422.1.

Example 136: (2R)-Piperidine-2-carboxvlic acid (6-oxo-2-phenvl-5.6-dihvdro-1H- f1.21diazepinof4,5.6-cdlindol-8-vl)-amide (hvdrochloric sait)

10 Step 1. Préparation of (2R)-2-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indol-8-ylcarbamoyl)-piperidine-1-carboxylic acid ierf-butyl ester 136(a)

Préparation of Intermediate 136(a) from the title compound of Example 7 (0.11 g, 0.4 mmol),(2R)-piperidine-1,2-dicarboxylic acid 1-terf-butyl ester (0.143 g, 0.6 mmol), triethylamine (0.3 mL,2 mmol), 15 O-(7-azabenzotriazol-1-yl)-W,/V,/\/’,/S/-tetramethyluroniurn hexafluorophosphate (0.23 g, 0.63mmol) and /V,W-dimethylformamide (0.1 M, 5 mL) was carried out analogously to Example 11.Silica gel chromatography afforded Intermediate 136(a) (0.21 g) as a yeilow powderih 88% yield.1H-NMR (de-DMSO): δ 12.09 (s, 1H), 10.40 (s, 1H), 10.11 (s, 1H), 8.10 (s, 1 H), 7.74-7.44 (m, 7H),4.64-4.55 (m, 1H), 3.83 (d, 1H, J= 12.25 Hz), 3.35-3.20 (buried m, 1H), 2.20-2.05 (m, 1H), 1.80- 20 1.50 (m,3H), 1.45-1.25 (bs, 11 H). LCMS: (M+H+) 488.2.

Step 2. Préparation of Title Compound: (2R)-Piperidine-2-carboxylic acid (6-oxo-2-phenyl- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-coQindol-8-yl)-amide (hydrochioric sait) 25 Préparation of the title compound from Intermediate 136(a) (0.16 g, 0.33 mmol) and 4M HCl indioxane (1.6 mL, 6.6 mmol) was carrïed out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titlecompound (0.137 g) as an orange/yellow powder in 96% yield. 1H-NMR (ds-DMSO): 5 12.31 (s, 1H), 10.90 (s, 1H), 10.45 (s, 1H), 9.26 (b, 1H), 8.80-8.75 (m, 1H), 30 8.11 (S, 1H), 7.76-7.46 (m, 7H), 3.95-3.81 (m, 1H), 3.35-3.25 (m, 1H), 3.10-2.92 (m, 1H), 2.36- 2.26 (m, 1H), 1.76-1.51 (m,5H). LCMS: (M+H+) 388.1. 013017 164

Example 137: (2S)-Piperidine-2-carboxvlic acid (6-oxo-2-phenvl-5,6-dihvdro-1 H- Π ,2idiazepinof4.5.6-cdlindol-8-vl)-amide (hydrochloric sait)

Step 1. Préparation of (2S)-2-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol·8-ylcarbamoyl)-piperidine-1-carboxylic acid iert-butyl ester 137(a)

Préparation of intemnediate 137(a) from the titie compound of Example 7 (0.138 g, 0.5 mmol),(2S)-Piperidine-1,2-dicarboxylic acid 1-iert-butyl ester (0.143 g, 0.6 mmol), triethylamine (0.3 mL,2 mmol), O-(7-azabenzotriazol-1-yl)-A/,/\/,/\/’,/\/-tetramethyluronium hexafluorophosphate (0.23 g,0.63 mmol) and W,W-dimethylformamide (0.1 M, 5 mL) was carried out analogously to Example11. Silica gel cbromatography afforded Intermediate 137(a) (0.20 g) as a yellow powder in 84%yield. 1H-NMR (de-DMSO): 5 12.09 (s, 1H), 10.40 (s, 1H), 10.11 (s, 1H), 8.10 (s, 1 H), 7.74-7.44 (m, 7H),4.64-4.55 (m, 1H), 3.83 (d, 1H, J= 12.25 Hz), 3.35-3.20 (buried m, 1H), 2.20-2.05 (m, 1H), 1.80-1.50 (m, 3H), 1.45-1.25 (bs, 11 H). LCMS: (M+H+) 488.1.

Step 2. Préparation of Titie Compound: (2S)-Piperidine-2-carboxyiic acid (6-oxo-2-phenyl- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc(Jindol-8-yl)-amide (hydrochloric sait)

Préparation of the titie compound from intermediate 137(a) (0.16 g, 0.33 mmol) and 4M HCl indioxane (1.6 mL, 6.6 mmol) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titiecompound (0.132 g) as an orange/yellow powder in 95% yield. 1H-NMR (d6-DMSO): δ 12.31 (s, 1H), 10.90 (s, 1H), 10.45 (s, 1H), 9.26 (b, 1H), 8.80-8.75 (m, 1H),8.11 (s, 1H), 7.76-7.46 (m, 7H), 3.95-3.81 (m, 1H), 3.35-3.25 (m, 1H), 3.10-2.92 (m, 1H), 2.36-2.26 (m, 1H), 1.76-1.51 (m, 5H). LCMS: (M+H+) 388.2.

Example 138: (2S.4R)-4-Hvdroxv-pyrrolidine-2-carboxvlic acid (6-oxo-2-phenvl-5,6-dihydro-1 H- H,21diazepinof4.5.6-cdlindol-8-v[)-amide fhvdrochloric sait)

138(a) 4N HCl (Dioxane) CH2CI2, 71%

013017 165

Step 1. Préparation of (2S, 4R)-4-Hydroxy-2-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cd]indol-8-ylcarbamoyl)-pyrrolidine-1-carboxylic acid terf-butyl ester138{a)

Préparation of Intermediate 138(a) from the title compound of Example 7 (0.138 g, 0.5 mmol),(2S, 4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-fert-butyl ester (0.144 g, 0.6 mmol),triethylamine (0.3 mL, 2 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,A/’/V-tetramethyluroniumhexafiuorophosphate (0.23 g, 0.63 mmol) and Λ/,/V-dimethylformamide (0.1 M, 5 mL) was carriedout analogously to Example 11. Silica gelchromatography afforded Intermediate 138(a) (0.127 g)as a yellow powder in 52% yield. 1H-NMR (ds-DMSO): δ 12.19 (s, 1H), 10.46 (s, 1H), 10.28 (s, 1H), 8.29 (s, 0.8H, major rotamer),8.29 (s, 0.2H, minor rotamer), 7.75-7.51 (m, 7H), 4.50-4.35 (m, 2H), 3.60-3.30 (m, 3H), 2.30-2.17(m, 1 H), 2.10-1,.90 (m, 1H), 1.48 (s, 2H, minor rotamer), 1.34 (s, 2H, major rotamer). LCMS: (M+H+) 490.1.

Step 2. Titie Compound: (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid (6-oxo-2-phenyl- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc(Jindol-8-yl)-amide (hydrochioric sait)

Préparation of the title compound from Intermediate 138(a) (0.105 g, 0.21 mmol) and 4M HCl indioxane (1 mL, 4.2 mmol) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titlecompound (0.065 g) as an orange/yellow powder in 71% yield. 1H-NMR (de-DMSO): δ 12.33 (s, 1H), 10.93 (s, 1H), 10.44 (s, 1H), 10.10-9.95 (m, 1H), 8.90-8.45(m, 1H), 8.08 (s, 1H), 7.75-7.45 (m, 7H), 4.75-4.35 (bm, 3H), 3.45-3.30 (m, 1H), 3.20-3.10 (m,1H), 2.50-2.35 (m, 1H), 2.10-1.95 (m, 1 H). LCMS: (M+H+) 390.1.

Example 139: (2S)- 2-Amino-3-cvano-/V-(6-oxo-2-phenvl-5,6-dihvdro-1H-ri,2]diazepinof4.5.6-

Step 1. Préparation of <1S)- [2-Cyano-1-(6-oxo-2-phenyi-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamoyl)-ethyl]-carbamic acid iert-butyl ester 139(a)

Préparation of Intermediate 139(a) from the title compound of Example 7 (0.138 g, 0.5 mmol),(2S)-2-fert-butoxycarbonylamino-3-cyano-propionic acid (0.134 g, 0.6 mmol), triethylamine (0.3mL, 2 mmol), O-(7-azabenzotriazol-1-yl)-/V,/\/,A/',/\/-tetramethyluronium hexafiuorophosphate (0.23 013017 166 g, 0.63 mmol) and /\/,A/-dimethylformamide (0.1 M, 5 mL) was carried out analogously toExample 11. Silica gel chromatography afforded Intermediate 139(a) (0.094 g) as a yellow powderin 40% yield. 1H-NMR (de-DMSO): δ 12.15 (s, 1H), 10.42 (s, 1H), 10.37 (s, 1H), 6.11 (s, 1H), 7.75-7.48 (m, 8H),4.55-4.40 (m, 1H), 3.02 (dd, 1H, J = 17.1, 4.9 Hz), 2.85 (dd, 1H, J= 17.0, 9.0 Hz), 1.43 (s, 9H). LCMS: (M+H+) 473.2.

Step 2. Préparation of Title Compound: (2S)- 2-Amino-3-cyano-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd|indol-8-yl)-propionamide acetic acid sait

Préparation of the title compound from Intermediate 139(a) (0.084 g, 0.18 mmol) and 4M HCl indioxane (0.9 mL, 3.6 mmol) was carried out analogously to Example 91. A préparative HPLCafforded the title compound (0.038 g) as an orange/yellow powder in 49% yield. 1H-NMR (de-DMSO): δ 12.31 (s, 1H), 10.50 (s, 1H), 10.35 (bs, 1H), 8.24 (s, 1H), 7.80-7.55 (m,7H), 3.84 (dd, 1H, J = 7.0, 6.9 Hz), 2.99 (dd, 1H, J = 16.8, 5.7 Hz), 2.85 (dd, 1H, J = 16.6, 7.2 Hz),2.73 (s, 6H). LCMS: (M+H+) 373.1.

Example 140: (2S)-<V-f6-Oxo-2-phenyl-5.6-dihydro-1H-[1.2ldiazepinol4,5.6-ccflindol-8-vl)-2- pyiTOlidin-2-vl-acetamide (hvdrochloric sait)

140{a)

Step 1. Préparation of (2S)-2-[(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamoyl)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester 140(a)

Préparation of Intermediate 140(a) from the title compound of Example 7 (0.138 g, 0.5 mmol),(2S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid ferf-butyl ester (0.143 g, 0.6 mmol),triethylamine (0.3 mL, 2 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,W,/\/',/\/-tetramethyluroniumhexafluorophosphate (0.23 g, 0.63 mmol) and /V,/V-dimethylformamide (0.1 M, 5 mL) was carriedout analogously to Example 11. Silica gel chromatography afforded Intermediate 140(a) (0.155 g)as a yellow powder in 64% yield. 1H-NMR (de-DMSO): δ 12.09 (s, 1H), 10.39 (s, 1H), 10.17 and 10.10 (2s, 1H, minor and majorrotamer), 8.20 (S, 1H), 7.75-7.45 (m, 7H), 4.10 (S, 1H), 4.20-4.05 (m, 1H), 3.50-3.25 (m, 2H),2.10-1.75 (m, 4H), 1.40 and 1.29 (2s, 9H, minor and major rotamer). LCMS: (M-Boc+H*) 388.2.

Step 2, Préparation of Title Compound: (2S)-W-(6-Oxo-2-phenyl-5,6-dihydro-1tf- [1,2]diazepino[4,5,6-cd]indol-8-yl)-2-pyrrolidm-2-yl-acetamide (hydrochloric sait) 013017 167

Préparation of the title compound from Intermediate 140(a) (0.1 g, 0.20 mmol) and 4M HCl indioxane (1 mL, 4.2 mmol) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titlecompound (0.055 g) as an orange/yellow powder in 63% yield. major rotamer; 1H-NMR (d6-DMSO): δ 12.23 (s, 1H), 10.48 (s, 1H), 10.41 (s, 1H), 9.25-9.10 (m,1H), 8.95-8.80 (m, 1H), 8.11 (s, 1H), 7.75-7.45 (m, 7H), 4.10 ( buried m, 1H), 3.90-3.75 (m, 1H),3.25-3.15 (m, 2H), 2.95-2.85 (m, 2H), 2.25-1.55 (m, 5H). minor rotamer; 1H-NMR (d6-DMSO): δ 12.31 (s, 1H), 10.92 (s, 1H), 10.45 (s, 1H), 9.85-9.75 (m,1 H), 8.75-8.60 (m, 1 H), 3.35-3.25 (m, 2H). LCMS: (M+H+) 388.2.

Example 141: (3R)-1.2.3.4-Tetrahvdro-isoquinoline-3-carboxvlic acid (6-oxo-5,6-dihvdro-1H- f1.21diazepinoF4.5.6-cdlindol-8-vl)-amide (hvdrochloric sait)

141 (a)

Step 1. Préparation of (3R) 3-(6-Oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cafJindol-8-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid feri-butyl ester 141(a)

Préparation of intermediate 141 (a) from the title compound of Example 2 (0.1 g, 0.5 mmol), (3R)-3,4-dihydro-1H-iëoquinoline-2,3-dicarboxyiic acid 2-feh-butyl ester (0.103 g, 0.6 mmol),triethylamine (0.3 mL, 2 mmol), O-(7-azabenzotriazol-1-yl)-A/,W,/V’,/V’-tetramethyluroniumhexafluorophosphate (0.23 g, 0.63 mmol) and W,/V-dimethylformamide (0.1 M, 5 mL) was carriedout analogously to Example 11. Silica gel chromatography afforded Intermediate 141 (a) (0.094 g)as a yellow powder in 41 % yield. 1H-NMR (de-DMSO): δ 11.72 (bs, 1H), 10.25 (s, 1 H), 10.14 (bs, 1H), 8.09 and 7.96 (2s, 1H, majorand minor rotamer), 7.57 (s, 2H), 7.47 (s, 1H), 7.30-7.10 (m, 4H), 4.75-4.60 (m, 1H), 4.48-4.34(m, 1H), 3.40-3.00 (m, 3H), 1.47 (s, 3H), 1.31(s, 6H). LCMS: (M-H+) 458.3.

Step 2. Préparation of Title Compound: (3R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylicacid (6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indoI-8-yl)-amide (hydrochloric sait)

Préparation of the title compound from Intermediate 141 (a) (0.094 g, 0.20 mmol) and 4M HCl indioxane (1 mL, 4.2 mmol) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titlecompound (0.051 g) as an orange/yellow powder in 63% yield. 013017 168 1H-NMR (de-DMSO): S 11.98 (s, 1H), 11.08 (s, 1H), 10.32 (s, 1H), 9.93 (b, 1H), 9.64 (b, 1H),8.09 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.29 (s, 5H), 4.50-4.10 (buried m, 3H), 3.53(dd, 1H, «7= 16.4, 4.0 Hz), 3.14 (dd, 1H, J= 16.8, 12.06 Hz). LCMS: (M+H+) 360.1.

Example 142: (2S, 4R)-4-Benzvloxy-pyrrolidine-2-carboxylic acid (6-oxo-5,6-dihvdro-1/7- H.21diazepinof4.5.6-cdlindol-8-vl)-amide fhvdrochloric sait)

Step 1. Préparation of (2S, 4R) 4-Benzyloxy-2-(6-oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-ccQindol-8-ylcarbamoyl)-pyrrolidine-1-carboxylic acid fert-butyl ester 142(a)

Préparation of intermediate 142(a) from the title compound of Example 2 (0.1 g, 0.5 mmol), (2S,4R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-ferf-butyl ester (0.103 g, 0.6 mmol),triethylamine (0.3 mL, 2 mmol), 0-(7-azabenzotriazol-1-yl)-W,/V,W’,A/’-tetramethyluroniumhexafluorophosphate (0.23 g, 0.63 mmol) and A/,7V-dimethylformamide (0.1 M, 5 mL) was carriedout analogously to Example 11. Silica gel chromatography afforded Intermediate 142(a) (0.126 g)as a yellow powder in 50% yield. 1H-NMR (d6-DMSO): δ 11.76 (s, 1H), 10.26 (s, 1H), 10.18 (s, 1H), 8.18 and 8.10 (s, 1H,rotamers), 7.60 (s, 1H), 7.58 (s, 1H), 7.48 (s, 1 H), 7.42-7.26 (m, 5H), 4.53 (s, 2H), 4.39-4.26 (m,1H), 4.22 (bs, 1 H), 3.54 (bs, 2H), 3.32 (s, 2H), 1.27 (s, 6H). LCMS: (M-H+) 502.2.

Step 2. Préparation of Title Compound: (2S, 4R)-4-Benzyioxy-pyrrolidine-2-carboxylic acid(6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide (hydrochloric sait)

Préparation of the title compound from Intermediate 142(a) (0.106 g, 0.21 mmol) and 4M HCl indioxane (1 mL, 4.2 mmol) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included a further trituration with CH2CI2/diethyl ether and afforded the titlecompound (0.085 g) as an orange/yellow powder in 92% yield. 1H-NMR (d6-DMSO): δ 11.96 (s, 1H), 10.94 (s, 1H), 10.33 (s, 1H), 10.12 (b, 1H), 8.89 (b, 1H),8.06 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.51 (S, 1H), 7.45-7.28 (m, 7H), 4.40 (b, 2H), 3.47 (b, 2H),2.80-2.65 (m, 1 H), 2.15-2.01 (m, 1 H). LCMS: (M+H+) 404.2.

Example_143:_(2ff)-2-Amino-3-(4-hvdroxvphenvl)-ft/-(6-oxo-2-phenyl-5.6-dihvdro-1/-/- 11,21diazepinof4,5.6-ccflindol-8-vl)propanamide hydrochloride

HN—N 013017 169 HO"

Préparation of example 143 from title compound of Example 150 (64 mg, 0.119 mmol), and 4MHCl in dioxane (5 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, included freebasing with triethylamine and subséquent silica gel chromatography elutingwith 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2CI2 (5mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, thetitle compound (32 mg, 0.067 mmol) was obtained as an orange/yellow powder in 57% yield. 1H NMR (de-DMSO): δ 12.25 (s, 1H, exchanges), 10.71 (s, 1H, exchanges), 10.45 (s, 1H,exchanges), 9.44 (br s, 1H, exchanges), 8.45-8.31 (br m, 2H, exchanges), 8,08 (s, 1H), 7.76-7.45(m, 7H), 7.09 (d, 2H, J= 8 Hz), 6.72 9d, 2H, J= 8 Hz), 4.13 (m, 1H), 3.19-2.97 (m, 2H). LCMS: (M+H+) 440.0, (M-H)'438.2.

Example 144: (S)-1-Methvl-pyrrolidine-2-carboxvlic acid (6-oxo-5, 6-dihvdro-1- f1,2ldiazepinof4,5.6-lindol-8-vl)-amide

HN-N

Préparation of example 144 from the title compound of Example 2 (190 mg, 0.95 mmol), N-methylproline (129 mg, 1.47 mmol), triethylamine (0.19 mL, 1.43 mmol), and O-(7-azabenzotriazol-1-yl)-A/,W,/V)A/’-tetramethyluronium hexafluorophosphate (470 mg, 1.3 mmol) inW,W-dimethylformamide (5 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 10 % methanol in CH2CI2), also in an analogous manner, affordedtitle compound (100 mg, 0.32 mmol) as a yellow powder in 34% yield. 1H NMR (dg-DMSO): 11.83 (s, 1H), 10.33 (s, 1H), 9.96 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.65 (s,1H), 7.55 (s, 1H), 3.20 (m, 1H), 3.03 (m, 1H), 2.63 (m, 1H), 2.23 (m, 1H), 1.91-1.88 (m, 3H).

Anai. Calcd for C16H17N5O2· 0.2 HZO: C, 61.02; H, 5.57; N, 22.24. Found: C, 60.83; H, 5.29; N,22.23. LCMS: (M+H+) 312.1.

Example 145: (2R)-5-Oxo-pvrrolidine-2-carboxvlic acid f6-oxo-5,6-dihvdro-1- f 1.21diazepinof4,5,61indol-8-vl)-amide 013017 170 10 15

Préparation of example 145 from the title compound of Example 2 (freebase) (190 mg, 0.95mmol), (R)-(+)-pyrrolidonecarboxylic acid (167 mg, 1.29 mmol), triethylamine (0.25 mL, 1.77mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V’,/V'-tetramethyluroniurn hexafluorophosphate (538mg, 1.42 mmol) in Λ/,/V-dimethylformamide (5 mL) was carried out analogously to Example 11.The mixture was concentrated and the residue was triturated with methanol. The resulting solidswere then collected by filtration and washed with methanol to give the title compound (220 mg,0.57 mmol) as a yellow powder in 60% yield. 1H NMR (ds-DMSO): 11.79 (s, 1H), 10.27 (s, 1 H), 10.20 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.62 (s,1H), 7.59 (s, 1H), 7.49 (s, 1 H), 4.21 (m, 1H), 2.36 (m, 1 H), 2.24-2.16 (m, 2H), 2.03 (m, 1H).

Anal. Calcd for C1SH13N5O3· 1 H2O: C, 54.71; H, 4.59; N, 21.27. Found: C, 54.51; H, 4.68; N,21.05. LCMS: (M+H+) 312.2.

Example 146: A/-(6-Oxo-5,6-dihvdro-1 H-f1,21diazepinof4,5,6-cc/lindol-8-vh-3-piperidin-4-vl- actvlamide acetic acid sait

Title Compoundof Example 2

20

Step 1. Préparation of 4-[2-(6-Oxo-5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cdlindol-8-ylcarbamoyl)-vinyl]-piperidine-1-carboxylic acid ferf-butyl ester 146(a)

Préparation of intermediate 146(a) from the title compound of Example 2 (freebase) (49 mg,0.245 mmol), 4-(2-carboxy-vinyl)-piperidine-1-carboxylic acid ferf-butyl ester (99 mg, 0.39 mmol),triethylamine (0.069 mL, 0.49 mmol), and O-(7-azabenzotriazol-1-yI)-/V,/V,A/',A/- 013017 171 10 15 tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) in W,W-dimethylformamide (3 mL)was carried out analogously to Example 11. Silica gel chromatography (eluted with 10 % methanolin CH2CI2), also in an analogous manner, afforded Intermediate 146(a) (58 mg, 0.13 mmol) as ayellow powder in 55% yield.

Step 2. Préparation of Title Compound: W-(6-Oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-3-piperidin-4-yl-acrylamide acetic acid sait

Préparation of the title compound from Intermediate 146(a) (58 mg, 0.13 mmol) in CH2CI2 (2 mL)and 4M HCl in dioxane (2 mL) was carried out analogously to Example 91. After concentration,the residue was purified by préparative HPLC (Peeke Scientific, Hl-Q C18 reverse phase 5u,100A, 250x21.2 mm column) eluting with CH3CN and 0.1% acetic acid in water at a flow rate of 20mL/min using a gradient of 5-95% CH3CN over 40 min to give the title compound (16 mg, 0.04mmol) as a pale yellow powder in 31 % yield. 1H NMR (d6-DMSO): 11.55 (s, 1H), 10.00 (s, 1H), 9.91 (s, 1H), 8.00 (s, 1H), 7.32 (d, J = 8 Hz,2H), 7.22 (s, 1H), 6.50 (m, 1H), 5.82 (m, 1H), 2.77-2.74 (m, 2H), 2.03 (m, 1H), 1.65-1.53 (m, 2H),1.29-1.28 (m, 2H), 1.10-1.02 (m, 2H). LCMS: (M+H+) 337.

Example 147: 8-terf-Butoxvcarbonvlamino-6-oxo-5,6-dihvdro-1H-l1.21diazepinof4.5,6-cdiindole-2- carboxvlic acid methvl ester 20

Intennediate 2(b),Example 2

NH2NH2H2O, AoOH

MeOH, reflux, 100%

Pd(dppf)CI2l MeOH—-:->.

Et3N, CO, DMF, 35%

HN-N

BocHN

Step 1. Préparation of 6-iert-ButoxycarbonyIamino-1H-indole-4-carboxylic acid tnethyl ester 147{a) 013017 172

Triethylamine (17.1 mL, 123 mmol) was added slowly to Intermediate 2(b) of Example 2(hydrochloride) (27.5 g, 121 mmol) cooled to 0 °C in 400 ml anhydrous CH3CN. After 0.5 hours,di-ferf-butyl dicarbonate (26.76 g, 123 mmol) in anhydrous CH3CN (50 mL) was added, and themixture was allowed to stir at room température for 24 h at which point volatile components wereremoved in vacuo. Ethyl acetate (500 mL) and H2O (500 mL) were added, and the aqueous layerwas extracted with ethyl acetate (4X120 mL). The combined ethyl acetate extracts were washedwith H2O (2X170 mL) and brine (100 mL) and allowed to dry over Na2SO4. Following filtration, thevolatile components were removed in vacuo to afford Intermediate 147(a) (35.1 g, 121 mmol) as abrown solid in quantitative yield. 1H NMR (de-DMSO): δ 12.28 (s, 1H), 9.43 (s, 1H), 7.91 (br s, 1H), 7.89 (s, 1H), 7.42 (t, 1 H, J =2.73 Hz), 6.83 (t, 1H, J = 2.17 Hz), 3.89 (s, 3H), 1.50 (s, 9H). LCMS: (M+Na+) 313.1 ; (M-H)' 289.2.

Anal. Calcd. for CisH18N2O4: C, 62.06; H, 6.25; N, 9.65.

Found: C, 62.08; H, 6.30; N, 9.59.

Step 2. Préparation of 6-fert-Butoxycarbonylamino-3-formyl-1W-indole-4-carboxylic acidmethyl ester 147(b) A premixed Vilsmeier reagent consisting of phosphores oxychloride (33.67 mL, 3624 mmol) inAf.W-dimethylformamide (81.40 mL) was added dropwise at 0 °C to Intermediate l47(a) (33.87 g,116 mmol) stirring in anhydrous CH2CI2 (584 mL). The mixture was stirred for 1 hour at roomtempérature, quenched with aqueous 2.0 M sodium acetate (700 ml) at 0 °C and neutralized withsolid Na2CO3. A solid formed and the mixture was partitioned between ethyl acetate (4000 mL)and H2O (2000 mL). The layers were separated and the aqueous layer was extracted with ethylacetate (4 X 500 mL). The organic layers were combined, washed with brine, dried over Na2SO4,filtered, and concentrated. Methanol (3500 mL) was added to the residue followed by K2CO3 (70g). The mixture was stirred at room température for 16 hours at which point volatile componentswere removed in vacuo. Ethyl acetate (500 mL) and H2O (500 mL) were added. The entiremixture was then filtered and the insoluble solids were collected and dried under vacuum to affordIntermediate 147(b) (14.35 g, 45.1 mmol) as a white solid. The aqueous layer was again extractedwith ethyl acetate (4X120 mL), and the ethyl acetate extracts were combined, washed with H2O(2X170 mL), brine and allowed to dry over Na2SO4. Following filtration, the volatile componentswere removed in vacuo to afford additional Intermediate 147(b) (10.74 g, 33.8 mmol) as a whitesolid. The combined yield for the two batches was 68%. 1H NMR (dB-DMSO): δ 12.28 (s, 1H), 10.09 (s, 1H), 9.60 (s, 1H), 8.23 (d, 1H, J- 3.01 Hz), 7.96(d, 1 H, J = 1.32 Hz), 7.65 (d, 1 H, J = 1.88 Hz), 3.84 (s, 3H), 1.50 (s, 9H). LCMS: (M+H+) 319, (M+Na+) 341.1; (M-H)’ 317.1

Step 3. Préparation of (6-Oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-carbamicacid fert-butyl ester 147(c) 013017 173

Acetic acid (7.89 ml) was added to Intermediate 147(b) (25.1 g, 78.9 mmol) in anhydrousmethanol (789 ml). The suspension was stirred at room température for 10 minutes andH2NNH2H2O (21.43 mL, 395 mmol) was added. The mixture was stirred at room température foranother 10 minutes, heated at 70 °C for 0.5 hours and cooled to room température. The volatilecomponents were removed in vacuo and the residual oil was triturated with methanol and tolueneto afford Intermediate 147(c) (23.6 g, 78.9 mmol) as a yellow powder in quantitative yield. 1H NMR (de-DMSQ): δ 11.63 (s, 1H), 10.19 (s, 1H), 9.45 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.51(d, 1H, J = 2.07 Hz), 7.44 (s, 1H), 1.49 (s, 9H). LCMS: (M+H*) 301.1, (M+Na*) 323.1; (M-H)' 299.1.

Anal. Calcd. for C15H16N4O3· 0.5 H2O: C, 59.10; H, 5.46; N, 18.38.

Found: C, 59.49; H, 5.43; N, 17.97.

Step 4. Préparation of (2-Bromo-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-ccflindol-8-yl)-carbamic acid fert-butyl ester 147(d)

Intermediate 147(c) (1.00 g, 3.33 mmol) was dissolved in anhydrous W./V-dimethylformamide (15ml) and cooled to -78 °C. N-Bromosuccinimide (0.564 g, 3.17 mmol) in anhydrous N,N-dimethylformamide (3.5 ml) was added dropwise over 2 min. The reaction mixture was allowed towarm to room température and stirred for 1 hour. Additional N-bromosuccinimide (0.337 g, 2.00mmol) in W,N-dimethylformamide (c.a. 1.5 mL) was then added in portions over a 0.5 hours periodto drive the reaction to completion. The reaction mixture was poured into H2O (70 mL), and a darksolid precipitated. The solid was collected by filtration and dried under vacuum to giveIntermediate 147(d) (0.95 g, 2.51 mmol) as dark solid in 75% yield. ’H NMR (d6-DMSO): δ 12.54 (s, 1H), 10.47 (s, 1H), 9.57 (s, 1H), 7.77 (s, 1H), 7.71 (d, 1H, J =1.70 Hz), 7.31 (s, 1 H), 1.53 (s, 9H). LCMS; (M+H*) 379.0, 381.0, (M+Na*) 401.0,403.0; (M-H)' 377.1, 379.1.

Anal. Calcd. for C^H^BrN^: C, 47.51 ; H, 3.99; N, 14.77.

Found: C, 47.42; H, 3.99; N, 14.51.

Step 5. Préparation of Title Compound: 8-ferf-Butoxycarbonylamino-6-oxo-5,6-dihydro-1H- [1,2]diazepino[4,5,6-cd]indole-2-carboxylic acid methyl ester

Intermediate 147(d) (0.200 g, 0.529 mmol), triethylamine (0.147 mL, 1.06 mmol) and anhydrousmethanol (2 mL) in anhydrous W,A/-dimethylformamide (2 ml) were purged with Ar. [1,1*-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (86.4 mg, 0.106 mmol) was added and COwas bubbled into the reaction mixture for 5 minutes. The reaction was then sealed and heated at85 °C for 16 hours. The mixture was filtered through a thin pack of diatomaceous earth and thefiitrate reduced in vacuo. Silica gel chromatography (eluted with 1:1 ethyl acetate: hexane)afforded the title compound (66 mg, 0.184 mmol) as a yellow powder in 35% yield. 013017 174 1H NMR (de-DMSO): δ 12.42 (s, 1H), 10.80 (s. 1H), 9.69 (s, 1H), 8.14 (s, 1H) 7.91 (s, 1K), 7.76(s, 1H), 3.92 (s, 3H), 1.49 (s, 9H). LCMS: (M+H+) 359.1, (M+Na+) 381.2; (M-H)' 357.0.

Example 148: 1-Amino-/V-(6-oxo-2-phenvl-5.6-dihvdro-1W1,21diazepinor4.5.6-cdlindol-8-vl)-2.3- dihvdro-1 H-indene-1 -carboxamide hydrochioride

Préparation of example 148 from title compound of Example 149 (52 mg, 0.097 mmol), and 4MHCl in dioxane (5 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (46 mg, 0.097 mmol) as a yellow powder in quantitative yield.1H NMR (de-DMSO): δ 12.42 (s, 1H), 10.60 (s, 1H), 10.20 (s, 1H), 9.05-8.86 (m, 3H), 8.23 (s, 1H),7.90-7.73 (m, 3H), 7.72-7.57 (m, 6H), 7.55-7.41 (m 2H), 3.42 (m, 1H), 3.31 (m, 1H), 3.08 (m, 1H),2.55 (m, 1 H, partially obscured). LCMS: (M+H+) 436.2, 419.2.

Example 149: 1.1-Dimethvlethvl 1-ff(6-oxo-2-phenyl-5,6-dihvdro-1H-f1,21diazepinoi4,5.6-ccflindol- 8-vl)aminoicarbonvl)-2,3-dihvdro-1 H-inden-1 -ylcarbamate

Préparation of example 149 from the title compound of Example 7 (hydrochioride) (52 mg, 0.17mmol), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2,3-dihydro-1H-indene-1-carboxylic acid (72mg, 0.26 mmol), triethylamine (0.071 mL, 0.51 mmol), and O-(7-azabenzotriazol-1-yl)-W,A/,/V',A/’-tetramethyluronium hexafluorophosphate (99 mg, 0.26 mmol) in CH2CI2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Exampte 11. Silica gelchromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (63 mg, 0.12 mmol) as a yellow powder in 69% yield. ’H NMR (de-DMSO): δ 12.05 (ε, 1H), 10.36 (s, 1H), 10.01 (m, 1H), 8.09 (m, 1H), 7.87-7.74 (m,2H), 7.70-7.62 (m, 2H), 7.63-7.53 (m, 2H), 7.52-7.47 (m, 2H), 7.31-7.22 (m, 3H), 3.08-2.95 (m,3H), 2.09 (m, 1H), 1.40 (m, 9H). LCMS: (M-H)' 534.0. 013017 175

Example 150: 1.1-Dimethvlethvl (1f?)-1-f(4-hvdroxvphenvl)methvn-2-oxo-2-r(6-oxo-2-phenvl-5,6- dihvdro-1A/-f1.2ldiazepinof4,5,6-cdlindol-8-vl)amino)ethvlcarbamate

Préparation of example 150 from the title compound of Example 7 (hydrochloride) (44 mg, 0.144mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-hydroxyphenyl)propanoic acid (46mg, 0.173 mmol), triethylamine (0.060 mL, 0.43 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V’,W-tetramethyluronium hexafluorophosphate (66 mg, 0.173 mmol) in CH2CI2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (74 mg, 0.137 mmol) as a yellow powder in 95% yield. 1H NMR (ds-DMSO): δ 12.11 (s, 1H), 10.41 (s, 1H), 10.20 (s, 1H), 9.20 (s, 1H), 8.17 (s, 1H), 7.71-7.45 (m, 7H), 7.14 (d, 2H, J = 8.50 Hz), 6.68 (d, 2H, J = 8.40 Hz), 4.24 (m, 1H), 2.94 (m, 1H), 2.72(m, 1H), 1.35 (s, 9H). LCMS: (M-H)' 538.1.

Example 151: 1.1-Dimethvlethvl (1ff)-1-f(4-hvdroxvphenvl)methvn-2-oxo-2-ff6-oxo-2-phenvl-5.6- dihvdro-1 H-l 12)diazepinol4.5,6-cdlindol-8-vl)amino1ethvl( methvDcarbamate

mmol), (2R)-2-[{[( 1,1 -dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (57 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/’,/V’-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2CI2 (0.4 mL) andW,W-dimethylformamide (0.4 mL) was carried out analogously to Exampie 11. Additional (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (14 mg,0.Ù47 mmol) and O-(7-azabenzotriazol-1-yl)-/V,/V,AT,/V-tetramethyluronium hexafluorophosphate(18 mg, 0.047 mmol) were added after 24 hours to drive the reaction to completion. Silica gelchromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (55 mg, 0.099 mmol) as a yellow powder in 78% yield. 1H NMR (de-DMSO) multiple : δ 12,10 (br s, 1H), 10.38 (br s, 1H), 9.20 (m, 1H), 8.13 (m, 1H),7.72-7.63 (m, 3H), 7.61-7.43 (m, 4H), 7.09-7.00 (m, 2H), 6.72-6.62 (m, 2H), 4.82-4.60 (m, 1H),3.19-3.08 (m, 1H), 2.93-2.85 (m, 1H), 2.80-2.62 (m, 3H), 1.37-1.21 (m, 9H). 013017 176 LCMS: (M+H+) 554.2, (M+Na+) 576.2 (M-H)' 552.0.

Example 152; 1,1-Dimethvlethvl (1/?)-1-r(4-fluorophenvl)methvl]-2-oxo-2-i(6-oxo-2-phenvl-5.6- dihvdro-1 H-f 1,2)diazepino(4.5,6-cdlindol-8-vl)amino)ethylcarbamate

5 Préparation of example 152 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-fluorophenyl)propanoic acid (54 mg,0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and 0-(7-azabenzotriazol-1-yl)-AZ,A/,A/;A/-tetramethyluronium hexafiuorophosphate (73 mg, 0.192 mmol) in CH2CI2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel 10 chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (61 mg, 0.113 mmol) as a yellow powder in 88% yield. 1H NMR (de-DMSO): δ 12.12 (s, 1 H), 10.42 (s, 1H), 10.25 (s, 1H), 8.18 (s, 1H), 7.71-7.46 (m, 7H),7.42-7.34 (m, 2H), 7.21-7.09 (m, 3H), 4.41 (m, 1H), 3.03 (m, 1H), 2.85 (m 1H), 1.34 (s, 9H). LCMS: (M-H)’ 540.2. 15 Example 153: 1,1-Dimethylethyl (1P)-1-i4-hvdroxyphenvl)-2-oxo-2-if6-oxo-2-phenvl-5,6-dihvdro- 1 H-\ 1,21diazepinof4,5.6-cdlindol-8-yl)aminolethvlcarbamate

Préparation of example 153 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134mmol), (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (54 mg, 20 0.202 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V- tetramethyluronium hexafiuorophosphate (77 mg, 0.202 mmol) in CH2CI2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (27 mg, 0.10 mmol) and O-(7-azabenzotriazol-1-yl)-/V,W,/V',A/-tetramethyluronium hexafiuorophosphate (39 mg, 0.10 mmol) 25 were added after 24 hours to drive the reaction to completion. Silica gel chromatography (elutedwith 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (48 mg,0.091 mmol) as a yellow powder in 68% yield. 1H NMR (de-DMSO): δ 12.11 (s, 1H), 10.40 (s, 1H), 10.30 (s, 1H), 9.46 (s, 1H), 8.12 (s, 1H), 7.71-7.48 (m, 7H), 7.33-7.27 (m, 2H), 6.80-6.69 (m, 2H), 5.22 (m, 1 H), 1.41 (s, 1 H). 30 LCMS: (M+H+) 526.2. 013017

Example 154: 1,1-Dimethylethyl (1R)-1-inaphthalen-2-vlmethvl)-2-oxo-2-f(6-oxo-2-phenvl-5.6- dihvdro-1/-/-f1,21diazepinof4,5.6-ccflindol-8-vl)amino)ethvlcarbamate 177

10 15

Préparation of example 154 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128mmol), (2R)-2-({((1,1-dimethylethyl)oxy]carbonyl}amino)-3-naphthalen-2-ylpropanoic acid (58 mg,0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',A/-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2CI2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gelchromatogrâphy (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the titlecompound (69 mg, 0.120 mmol) as a yellow powder in 94% yield. 1H NMR (d6-DIVISO): δ 12.12 (s, 1H), 10.41 (s, 1 H), 10.31 (s, 1H), 8.18 (s, 1H), 7.90-7.81 (m, 4H),7.71-7.66 (m, 3H), 7.62-7.56 (m, 3H), 7.54-7.46 (m, 4H), 7.23 (d, 1 H, J = 8.1 Hz), 4.46 (m, 1H),3.23 (m, 1H), 3.02 (m, 1H), 1.30 (s, 9H). LCMS: (Μ-H)' 572.2.

Example 155:1.1-Dimethylethvl (1/?M-[(4-hydroxvphenv0methvn-2-oxo-2-l(6-oxo-5.6-dihydro-1H- f1.2Tdiazepinof4.5,6-ccflindol-8-vl)amino1ethvlcarbamate

HN-N

20 *

Préparation of example 155 from the title compound of Example 2 (71 mg, 0.30 mmol), (2/?)-2-({{(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-hydroxyphenyl)propanoic acid (121 mg, 0.45mmol), triethylamine (0.125 mL, 0.9 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V’,/V-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) in CH2CI2 (0.5 mL) and N,N-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Purification, also in ananalogous manner (eluted with 1:1 hexane:acetone) afforded the title compound (100 mg, 0.22mmol) as a yellow powder in 72% yield. 1H NMR (d6-DMSO): δ 11.75 (s, 1H), 10.26 (s, 1H), 10,13 (s, 1H), 9.19 (s, 1H), 8.16 (s, 1H), 7.61- 7.56 (m, 2H), 7.14 (d, 2H, J = 8.10 Hz), 7.04 (d, 1H, J = 8.48 Hz), 6.66 (d, 2H, J = 8.10 Hz), 4.22 (m, 1H), 3.08 (m, 1H), 2.87 (m, 1H), 1.34 (s, 9H). LCMS: (M+H+) 464.2, (M+Na+) 486.2. 25 013017

Example 156: 1.1-Dimethvlethvl f1R)-1-K4-hvdroxvphenvl)methvl1-2-oxo-2-i{6-oxo-5.6-dihvdro- 1H-f1.2ldiazepinof4.5.6-ccfiindol-8-vl)amino1ethvl(methvl)carbamate

HN—N 178 HO'

Préparation of example 156 from the title compound of Example 2 (74 mg, 0.31 mmol), (2R)-2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-3-(4-hydroxyphenyl)propanoic acid (138 mg,0.47 mmol), triethylamine (0.130 mL, 0.93 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/V,/V'/V-tetramethyluronium hexafluorophosphate (179 mg, 0.47 mmol) in CH2CI2 (0.5 mL) and N,N-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Purification, also in ananalogous manner (eluted with 1:1 hexane:acetone) afforded the title compound (131 mg, 0.27mmol) as a yellow powder in 88% yield. 1H NMR (d6-DMSO): δ 11.77 (s, 1H), 10.26 (s, 1H), 9.21 (s, 1H), 8.12 (m, 1H), 7.65 (d, 1H, J =1.32 Hz), 7.58 (d, 1H), J = 2.26 Hz), 7.48 (s, 1H), 7.07 (d, 2H, J = 8.29 Hz), 6.73-6.64 (m, 2H),4.75 (m, 1H), 3.12 (m, 1 H), 2.86-2.65 (m, 4 H, partially obscurred by Λ/,/V-dimethylformamide),1.35-1.25 (m, 9H). LCMS: (M+H+) 478.3, (M+Na+) 500.3.

Example 157: 1,1-Dimethylethvl (1P?)-1-f(4-fluorophenvl)mettivn-2-oxo-2-ff6-oxo-5,6-dihvdro-1H- ft,2)diazepinof4.5.6-cdlindol-8-vDaminolethvlcarbamate

HN-N

Préparation of example 157 from the title compound of Example 2 (80 mg, 0.34 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-fluorophenyl)propanoic acid (145 mg, 0.51 mmol),triethylamine (0.142 mL, 1.02 mmol), and O-(7-azabenzotriazol-1-yl)-A/,W,/V’,/V-tetramethyiuronium hexafluorophosphate (193 mg, 0.51 mmol) in CH2CI2 (0.5 mL) and Λ/,/V-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Purification, also in ananalogous manner (eluted with 1:1 hexane:acetone) afforded the title compound (56 mg, 0.12mmol) as a yellow powder in 35% yield. 1H NMR (d6-DMSO): δ 11.73 (s, 1H), 10.24 (s, 1H), 10.16 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H with fine splitting), 7.45 (s, 1H), (7.38-7.29 (m, 2H), 7.16-7.04 (m, 3H), 4.25 (m, 1H), 2.97 (m, 1H), 2.79 (m, 1H), 1.30 (s, 9H). LCMS: (M+H+) 466.2, (M+Na+) 488.3. 013017

Example 158: 1,1-Dimethylethvl f1ffl-1-(naphthalen-2-vlmethvl)-2-oxo-2-i(6-oxo-5,6-dihydro-1H- f1.21diazepinof4,5,6-cd|indol-8-vl)aminolethvlcarbamate 179

Préparation of example 158 from the title compound of Example 2 (76 mg, 0.32 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-naphthalen-2-ylpropanoic acid (145 mg, 0.48 mmol),triethylamine (0.134 mL, 0.96 mmol), and O-(7-azabenzotriazol-1-yl)-N,W,W',W-tetramethyluronium hexafluorophosphate (182 mg, 0.48 mmol) in CH2CI2 (0.5 mL) and N,N-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Purification, also in ananalogous manner (eluted with 1:1 hexane:acetone) afforded the title compound (67 mg, 0.13mmol) as a yellow powder in 42% yield. 1H NMR (ds-DMSO): δ 11.76 (br s, 1H), 10.27 (s, 1H), 10.27 (br s, 1H), 8.15 (s, 1H), 7.90-7.79 (m,4H), 7.62-7.42 (m, 5H), 7.21 (d, 1H, J = 7.73 Hz), 4.43 (m, 1H), 3.18 (m, 1H), 3.02 (m, 1H), 1.29(s, 9H). LCMS: (M+H+) 498.2, (M+Na+) 520.2.

Example 159: 1,1-Dimethylethvl (1R)-2-oxo-2-f(6-oxo-5,6-dihydro-1R-f1.2)diazepinof4.5.6- ccflindol-8-v0amino1-1 -fffphenylmethvDoxvImethvItethvlcarbamate

Préparation of example 159 from the title compound of Example 2 (97 mg, 0.41 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-[(phenylmethyl)oxy]propanoic acid (182 mg, 0.62mmol), triethylamine (0.171 mL, 1.23 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/\/-tetramethyluronium hexafluorophosphate (236 mg, 0.62 mmol) in CH2CI2 (0.5 mL) and N,N-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Purification, also in ananalogous manner (eluted with 1:1 hexane:acetone) afforded the title compound (40 mg, 0.083mmol) as a yellow powder in 20% yield. 1H NMR (ds-DMSO): δ 11.78 (br s, 1H), 10.29 (s, 1H), 10.22 (s, 1H), 8.14 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H, with fine splitting), 7.75 (s, 1H), 7.38-7.26 (m, 4H), 7.08 (d, 1H, J = 6.02 Hz), 4.54 (s, 2H), 4.42 (m, 1H), 3.74-3.63 (m, 2H), 1.42 (s, 9H). LCMS: (M+H+) 478.3, (M+Na+) 500.2.

Example 160: (1R.2R)- 6-Oxô-8-f(2-phenvl-cvclODropanecarbonvl)-amino1-5,6-dihvdro-1A/- ri.21diazepinof4,5,6-cdlindole-2-carboxvlic acid methyl ester 013017 180

5 Step 1. Préparation of 8-Amino-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-2-carboxyiic acid methyl ester (hydrochloric sait) 160(a)

Préparation of intermediate 160(a) from the title compound of Example 147 (45.0 mg, 0.125mmol) and 4.0 M HCl in dioxane (0.32 mL) was carried out analogously to Example 91. Isolation,also in an analogous manner, afforded Intermediate 160(a) (36.9 mg, 0.125 mmol) as a yellow 10 powder in 99% yield.

Step 2. Préparation of Title Compound: (1R,2R)- 6-Oxo-8-[(2-phenyl- cyclopropanecarbonyl)-amino]-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cd]indole-2-carboxylicacid methyl ester

Préparation of the title compound from Intermediate 160(a) (36.9 mg, 0.125 mmol), (1R,2R)-2- 15 phenyl-cyclopropanecarboxylic acid (22.0 mg, 0.136 mmol), triethylamine (0.175 mL, 1.26 mmol),and O-(7-azabenzotriazol-1-yl)-A/,/V,A/’,W-tetramethyluronium hexafluorophosphate (72.0 mg,0.189 mmol) in MW-dimethylformamide (2.0 mL) was carried out analogously to Example 11.Silica gel chromatography (elutéd with 1:1 ethyl acetate: hexane), also in an analogous manner,included a further trituration with methanol and ether and afforded the title compound (23 mg, 20 0.0572 mmol) as a yellow powder in 46% yield. 1H NMR (ds-DMSO): δ 12.53 (s, 1H), 10.83 (s, 1H), 10.58 (s, 1H), 8.23 (à, 1H, J = 1.51 Hz), 8.15(s, 1H), 7.76 (d, 1H, J = 1.51 Hz), 7.37-7.25 (m, 2H), 7.25-7.14 (m, 3H), 3.93 (s, 3H), 2.45-2.35(m, 1H), 2.15-2.05 (m, 1H), 1.58-1.47 (m, 1H), 1.45-1.33 (m, 1H). LCMS: (M+H+) 403.3, (M+Na+) 425.1; (M-H)' 401.0. 25 HRMS: (M+H+) calcd for C22H19N4O4, 403.1406, found 403.1413. 013017

Example 161: (2-Methvlcarbamovl-6-oxo-5,6-dihvdro-1W-f1.21diazepino|'4.5.6-ccnindol-8-vl)- carbamic acid terf-butvl ester 181

Inteimediate 147(d),Example 147

Pd(dppf)CI2, CH3NH2 -T —*·

Et3N, CO, DMF.29% HN—N O=s/ (Γι' NHMe "N H Ό

Préparation of example 161 was carried out in a manner analogous to step 5 of Example 147,except that methylamine hydrochloride was substituted for methanol. Thus CO was bubbledthrough a mixture of Intermediate 147(d) from Example 147 (200 mg, 0.529 mmol), triethylamine(0.29 mL, 2.11 mmol), methylamine hydrochloride (71 mg, 1.06 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (86 mg, 0.106mmol). Reaction conditions,work up and silica gel chromatography (eluted with 46:4:25 dichloromethane: methanol: ethylacetate) were also carried out in an analogous manner and afforded the title compound (55 mg,0.154 mmol) in 29% yield. 1H NMR (d6-DMSO): δ 12.01 (s, TH), 10.55 (s, 1H), 9.58 (s, 1H), 8.33-8.25 (m, 1H) 7.98 (s, 1H),7.80 (s, 1H), 7.71 (d, 1H, J= 1.51 Hz), 2.81 (d, 3H, J = 4.52 Hz), 1.48 (s, 9H). LCMS: (M+H+) 358.3, (M+Na+) 380.1; (M-H‘) 356.1.

Example 162: F2-f2-Hvdroxv-ethvlcarbamoyl)-6-oxo-5,6-dihvdro-1 H-[1.2ldiazepinof4.5,6-cd|indol- 8-vll-carbamic acid terf-butvl ester

Préparation of example 162 was carried out in a manner analogous to step 5 of Example 147,except that 2-aminoethanol was substituted for methanol, and chromatography was not required.Thus CO was bubbled through a mixture of intermediate 147(d) from Example 147 (60 mg, 0.16mmol), triethylamine (0.044 mL, 0.32 mmol), 2-aminoethanol (19 mg, 0.32 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (26 mg, 0.032 mmol) in N, N-dimethylformamide (3.0 mL). After the reaction was complété, the mixture was filtered throughdiatomaceous earth. The filtrate was concentrated, and methanol was added. The resulting solidswere collected by filtration and washed with methanol, dichloromethane and diethyl ether. Afterdrying under vacuum, the title compound (24 mg, 0.062 mmol) was obtained as a yellow powderin 39% yield. 1H NMR (ds-DMSO): δ 12.0Θ (s, 1H), 10.56 (s, 1H), 9.58 (s, 1H), 8.30 (t, 1H, J = 5.84 Hz) 8.06 (s,1H), 7.79 (s, 1H), 7.74 (s, 1H), 4.80 (br s, 1H), 3.60-3.48 (m, 2H), 3.38 (m, 2H, partially obscured),1.48 (s, 9H). LCMS: (M+H+) 388.1, (M+Na+) 410.1. 013017

Example 163: (1.2-frans)-2-Piperidin-4-vl-cvclopropanecarboxvlic acid (6-oxo-5, 6-dihydro-1H- ri.2ldiazepinof4.5.6-cdlindol-8-vl)-amide (acetic acid sait) 182

BocN /f

ÎO2Et NaH, Me3SO+l' DMSO,67% COjEt 1M LiOH, THF, H2O- 100% 163(a)

10 15 20

Step 1. Préparation of 4-((1,2-trans)-2-Ethoxycarbonyl-cyclopropyl)-piperidine-1-carboxylicacid fert-butyl ester 163(a)

To a mixture of NaH (303 mg, 7.57 mmol) and trimethylsulfoxonium iodide (1.67 g, 7.57 mmol)was added dimethyl sulfoxide (10 mL). After stirring for 30 min, a solution of 4-(2-ethoxycarbonyl-vinyl)-piperidine-1-carboxylic acid fert-butyl ester in dimethyl sufoxide (5 mL) was added drop-wise. After stirring ovemight, ethyl acetate and water were added to the mixture. The aqueouslayer was extracted with ethyi acetate several times. The combined organic layers were dried overNa2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography elutingwith 10% ethyl acetate/hexane to give Intermediate 163(a)(1.16 g, 67%).

Step 2. Préparation of 4-((1,2-Érans)-2-Carboxy-cyclopropyl)-piperidine-1-carboxylic acidfert-butyl ester 163(b)

To a mixture of Intermediate 163(a) (555 mg, 1.87 mmol) in 3:1 tetrahydrofuran-H2O (12 mL) wasadded aqueous 1M LiOH (5.61 mL). The resulting mixture was stirred ovemight. The mixture wasthen acidified with 1M HCl to pH 1 and extracted with several times with ethyl acetate. Thecombined organic layers was then washed with brine and concentrated to give Intermediate163(b) (515 mg, 1.87 mmol) in quantitative yield which was carried on without further purification.Step 3. Préparation of 4-[(1,2-frans)-2-{6-Oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cdJindol-8-ylcarbamoyl)-cyclopropyI]-piperidine-1-carboxylic acid fert-butyl ester 163(c) 013017 183

Préparation of Intermediate 163(c) from the title compound of Example 2 (freebase) (374 mg,1.87 mmol), Intermediate 163(b) (500 mg, 1.87 mmol), triethylamine (0.31 mL, 2.24 mmol), andO-(7-azabenzotriazol-1-yl)-/\/,W,A/',W'-tetramethyluronium hexafluorophosphate (782 mg, 2.06mmol) in W,/V-dimethylformamide (10 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 40% acetone in hexane), also in an analogous manner, affordedIntermediate 163(c) as a yellow powder (649 mg, 1.44 mmol) in 77% yield.

Step 4. Préparation of Title Compound: (1,2-frans)-2-Piperïdin-4-yl-cyclopropanecarboxylicacid (6-oxo-5, 6-dihydro-1-[1,2]diazepino[4,5,6]indol-8-yl)-amide (acetic acid sait)

Préparation of the title compound from Intermediate 163(c) (603 mg, 1.34 mmol) in CH2CI2 (10mL) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Afterconcentration, the crude product was purified by préparative HPLC in a manner analogous toExample 146, Step 2, to give the title compound as a pale yellow powder (37 mg, 0.09 mmol) in7% yield. 1H NMR (d6-DMSO): 11.71 (s, 1H), 10.26 (s, 1H), 10.23 (s, 1H), 8.11 (s, 1H), 7.55 (d, J = 8 Hz,2H), 7.46 (s, 1H), 3.05-3.03 (m, 2H), 2.51 (m, 1H), 1.65-1.53 (m, 3H), 1.29-1.28 (m, 2H), 1.10 (m,1H), 0.99 (m, 1H), 0.96 (m, 1H), 0.73 (m, 1H). LCMS: (M+H+) 352.

Example 164: (6-Oxo-2-vinvl-5.6-dihvdro-1H-f1.21diazepinof4.5.6-cd1indol-8-vl)-carbamic acid tert- butvl ester

Intermediate 147(d), <n-Bu)3SnCH=CH2Exampfe 147

Pd(PPh3)4, DMF, 85 °C

HN-N

BocHN

99%

Under an argon atmosphère, Intermediate 147(d) of Example 147 (0.250 g, 0.661 mmol), tributyl-vinyl-tin (0.420 g, 1.32 mmol) and tetrakis(triphenylphosphine)palladîum(0) (38 mg, 0.033 mmol)in anhydrous /V,/U-dimethylformamide (5 mL) were heated at 85 °C for 16 hours. The reaction wasfiltered through a thin pack of diatomaceous earth, and the filtrate concentrated in vacuo. Silicagel chromatography (eluted with 1:4 ethyl acetate: dichloromethane) afforded the title compound(0.18 g, 0.552 mmol) as a yellow powder in 84% yield. 1H NMR (de-DMSO): δ 11.80 (s, 1H), 10.32 (s, 1H), 9.51 (s, 1H), 7.72-7.62 (m, 3H), 7.05 (dd, 1H,J= 11.87, 6.59 Hz), 5.89 (d, 1H, J= 17.33 Hz), 5.43 (d, 1H, J= 11.11 Hz), 1.49 (s, 9H). LCMS: (M+H+) 327.2, (M+Na+) 349.1. 013017 184

Example 165: f2-(2-Dimethvlamino-ethvlcarbamovl)-6-oxo-5,6-dihydro-1 H-\ 1,21diazeplnof4,5,6- cdlindol-8-vn-carbamic acid fert-butvl ester

HN—N

BocHN

10 15

Préparation of example 165 was carried out in a manner analogous to step 5 of Example 147,except that /V,/V-dimethylethylenediamine was substituted for methanol. Thus CO was bubbledthrough a mixture of Intermediate 147(d) from Example 147 (1.5 g, 3.97 mmol), triethylamine (1.1mL, 7.92 mmol), W,W-dimethylethylenediamine (0.7 g, 7.94 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.65 g, 0.796 mmol) in N,N-dimethylformamide (30.0 mL). Reaction conditions, work up and silica gel chromatography (elutedwith 46:4:25 dichloromethane: methanol: ethyl acetate) were also carried out in an analogousmanner and afforded the title compound (1.25 g, 3.02 mmol) in 76% yield. 1K NMR (de-DMSO): δ 10.55 (s, 1H), 9.59 (s, 1H), 8.25 (t, 1H, J = 5.65, 4.71 Hz) 8.06 (s, 1H),7.80 (s, 1H), 7.74 (s, 1H), 3.45-3.37 (m, 2H, partially obscured), 2.42 (t, 2H, J = 6.59, 6.41 Hz),2.20 (s, 6H), 1.49 (s, 9H). LCMS: (M+H+) 415.3, (M+Na+) 437.1; (M-H)'413.1.

Example 166: (2R.3R)-2-Phenvl-pyrrolidine-3-carboxvlic acid (6-oxo-5,6-dihvdro-1H- ri.21diazepinof4.5,6-cdIindol-8-vl)-amide (hvdrochloric sait)

Title Compoundof Example 2 ->. HATU, EtgN, DWIF, 68%

4N HCl (Dioxane)->. CH2CI2, 99%

20

Step ï. Préparation of 2-Phenyl-pyrrolidine-1,3-dicarboxyiic acid 1-te/ï-butyl ester 166(a)

To a suspension of (2R,3R)-3-phenylpyrrolidine-2-carboxylic acid (100 mg, 0.556 mmol) indioxane (2 mL) and H2O (2 mL) was added triethylamine followed by di-tert-butyl dicarbonate (127mg, 0.583 mmol). The resulting mixture was stirred ovemight. The mixture was then partitionedbetween ethyl acetate and 0.1 M HCl. The combined organic layers were dried over anhydrous 013017 185

Na2SO4, filtered, and concentrated to give Intermediate 166(a) (162 mg, 0.56mmol) in 100%yield which was carried on without purification.

Step 2. Préparation of 3-(6-Oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamoyl)-2-phenyl-pyrrolidine-1-carboxylic acid /erf-butyl ester 166(b)

Préparation of intermediate 166(b) from the title compound of Example 2 (300 mg, 1.0 mmol),Intermediate 166(a) (162 mg, 0.56 mmol), triethylamine (0.15 mL, 1.1 mmol), and O-(7-azabenzotriazol-1-yl)-A/,W,/V’,/V-tetrariiethyluronium hexafluorophosphate (254 mg, 0.667 mmol) inW,A/-dimethylformamide (10 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 40% acetone in hexane), also in an analogous manner, affordedIntermediate 166(b) as a yellow powder (180 mg, 0.38 mmol) in 68% yield.

Step 3. Préparation of Title Compound: (2R,3R)-2-Phenyl-pyrrolidine-3-carboxylic acid (6-oxo-5,6-dihydro-1tf-[1,2]diazepino[4,5,6-cd]indoI-8-yl)-amide (hydrochloric sait)

Préparation of the title compound from Intermediate 166(b) (180 mg, 0.38 mmol) in CH2CI2 (5 mL)and 4M HCl in dioxane (5 mL) was carried out analogously to Example 91. The solids werecollected by filtration and washed with diethyl ether to give the title compound as a pale yellowpowder (154 mg, 0.37 mmol) in 99% yield. 1H NMR (de-DMSO): 12.03 (s, 1H), 10.72 (s, 1H), 10.46 (s, 1H), 10.20 (br s, 1H), 9.24 (brs, 1H),8.17 (s, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.58-7.52 (m, 5H), 7.48 (m, 1H),4.43 (m, 1H), 3.77 (q, J= 8.0 Hz, 1H), 3.75 (m, 1H), 3.59 (m, 1H), 2.66 (m, 1H), 2.62 (m, 1H).LCMS: (M+H+) 374.2.

Example 167: (2R)-3-f4-Hvdroxyphenvl)-2-(methvlamino)-/V-(6-oxo-2-phenvl-5.6-dihvdro-1 H- f1.2ldiazepinof4.5.6-cdlindol-8-vl)propanamide hvdrochloride

4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included freebasing with triethylamine and subséquent silica gelchromatography eluting with 3:1:1 hexane:ethyi acetate:ethanol. With ice bath cooling, the purifiedfreebase in CH2CI2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of thevolatile components, the title compound (20 mg, 0.041 mmol) was obtained as an orange/yellowpowder in 48% yield. 1H NMR (ds-DMSO): δ 12.21 (s, 1H), 10.70 (s, 1H), 10.43 (s, 1H), 9.44-9.06 (m, 1H), 8.02(s, 1H),7.72-7.64 (m, 2H), 7.61-7.54 (m, 3H), 7.53-7.47 (m, 2H) 7.05 (d, 2H, J = 8.0 Hz), 6.65 (d, 2H, J = 013017 186 8.0 Hz), 4.09 (m, 1H), 3.40-3.31 (m, 2H), 3.16 (dd, 1H, J = 6.07, 13.90 Hz), 3.07 (dd, 1 H, J =7.58,13.89 Hz), 2.55 (s, 3H). LCMS: (M+H+) 454.1, (M+Na+) 476.1.

Example_168:_(2R)-2-Amino-3-(4-fluorophenvl)-/V-(6-oxo-2-phenyl-5.6-dihvdro-1H- H.21diazepinof4.5.6-cdlindol-8-vl)propanamide hvdrochloride

10 15

Préparation of example 168 from the title compound of Example 152 (49 mg, 0.091 mmol) and4M HCl in dioxane (10 mL) was camed out analogously to Example 91. Isolation, also in ananalogous manner, included freebasing with triethylamine and subséquent silica gelchromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooiing, the purifiedfreebase in CH2CI2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of thevolatile components, the title compound (21 mg, 0.044 mmol) was obtained as an orange/yellowpowder in 49% yield. 1H NMR (de-DMSO): δ 12.26 (s, 1H), 10.83 (s, 1H), 10.46 (s, 1H), 8.48 (br ε, 3H), 8.08 (s, 1H),7.73-7.48 (m, 7H), 7.40-7.30 (m, 2H), 7.24-7.13 (m, 2H), 4.22 (m, 1H), 3.24 (m, 1H), 3.13 (m, 1H).LCMS: (M+H*) 442.1, (M+Na*) 464.1.

Example 169: (1R.2R)- 6-Oxo-8-f(2-phenyl-cvctopropanecarbonvl)-amino1-5,6-dihvdro-1H- f1.21diazepinof4,5.6-cdlindole-2-carboxvlic acid methvlamide

Intermediate 161(a),Example 161

HN-N

NHMe 4N HCl (Dioxane)->. CH2CI2, 99%

169(a) 20 Step 1. Préparation of 8-Amino-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(jindole-2- carboxylic acid methylamide (hydrochloric sait) 189(a)

Préparation of intermediate 169(a) from 161(a) of Example 161 (55.0 mg, 0.154 mmol) and 4.0 M HCl in dioxane (0.77 mL) was carried out analogously to Example 91. Isolation, also in an 013017 187 10 15 20 analogous manner, afforded Intermediate 169(a) (45.0 mg, 0.154 mmol) as a yellow powder in99% yield. ’H NMR (d6-DMSO): δ 12.46 (s, 1H), 10.71 (s, 1H), 8.54 (m, 1H), 8.05 (s, 1H), 7.43 (s, 1H), 7.34(s, 1 H), 2.81 (s, 3H). LCMS: (M+H+) 258.1 ; (M-H)' 256.1.

Step 2. Préparation of Title Compound: (1R,2R)- 6-Oxo-8-[(2-phenyl- cyclopropartecarbonyl)-amino]-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(Jindole-2-carboxylicacid methylamide

Préparation of the title compound from Intermediate 169(a) (45.0 mg, 0.154 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (59.4 mg, 0.231 mmol), triethylamine (0.086 mL, 0.616mmol), and 0-(7-azabenzotriazol-1-yl)-/V,A/,W’/V-tetramethyluronium hexafluorophosphate (87.8mg, 0.231 mmol) in W,W-dimethylformamide (2.0 mL) was carried out analogously to Example 11.When the reaction was judged complété, A/,A/-dimethylformamide was evaporated and methanolwas added. The mixture was filtered to collect the solids, which were washed with methanol anddiethyl ether. After drying under vacuum, the title compound (25.0 mg, 0.0623 mmol) wasobtained as a yellow powder in 41 % yield. 1H NMR (dB-DMSO): δ 12.13 (s, 1H), 10.60 (s, 1H), 10.51 (s, 1H), 8.36 (d, 1H, J = 4.52 Hz), 8.17(s, 1H), 8.01 (s, 1H), 7.70 (s, 1H), 7.37-7.25 (m, 2H), 7.25-7.14 (m, 3H), 2.83 (d, 3H, J = 4.52 Hz),2.45-2.35 (m, 1H), 2.14-2.04 (m, 1H), 1.57-1.47 (m, 1H), 1.45-1.33 (m, 1H). LCMS: (M+H+) 402.1, (M+Na+) 424.1. HRMS: (M+H+) calcd for C22H20N5O3, 402.1566, found 402.1551.

Example 170: (1R.2R)- 6-Oxo-8-i(2-phenvl-cvclopropanecarbonvh-amino1-5,6-dihvdro-1H- f1,21diazepinof4,5,6-cd1indole-2-carboxvlic acid f2-hvdroxv-ethv0-amide 4 N HCl (Dioxane)

Intermediate 162 (a), ->.

Example 162 CH2CI2,99%

HN—N

25

Step 1. Préparation of 8-Amino-B-oxo-5,6-dihydro-1H-[1,2)diazepino[4,5,6-cd]indoIe-2·carboxyiic acid (2-hydroxy-ethyl)-amide (hydrochloric sait) 170(a) 013017 188 10 15 20

Préparation of intermediate 170(a) from intermediate 162(a) of Example 162 (80.0 mg, 0.206mmol) and 4.0 M HCl in dioxane (1.10 mL) was carried out analogously to Example 91. Isolation,also in an analogous manner, afforded Intermediate 170(a) (66.7 mg, 0.206 mmol) as a yellowpowder in 99% yield. LCMS: (M+H+) 288.2.

Step 2. Préparation of Title Compound: (1R,2R)- 6-Oxo-8-[(2-phenyl- cyclopropanecarbonyl)-amino]-5,6-dihydro-1H-f1,2]diazepino[4,5,6-ctflindole-2-carboxylicacid (2-hydroxy-ethyl)-amide

Préparation of the title compound from intermediate 170(a) (66.7 mg, 0.206 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (46.0 mg, 0.284 mmol), triethylamine (0.143 mL, 1.03 mmol),and O-(7-azabenzotriazol-1-yl)-/y,W,W'Af'-tetramethyluronium hexafluorophosphate (147 mg,0.387 mmol) in W.W-dimethylformamide (2.0 mL) was carried out analogously to Example 11. Thereaction mixture was reduced in volume and subjected to préparative HPLC (H1-Q C18 reverse-phase 5 uM, 100A, 150x20 column eluting with CH3CN/0.1% aceticacid in H2O at a flowrate of 20mL/min using a gradient of 20-60% CH3CN over 30 min) to afford the title compound (15 mg,0.0348 mmol) as a yellow powder in 17% yield. 1H NMR (de-DMSO); δ 12.19 (s, 1H), 10.61 (s, 1H), 10.52 (s, 1H), 8.36 (t, 1H, J= 5.65 Hz), 8.18(d, 1H, J= 1.70 Hz), 8.09 (s, 1H), 7.70 (d, 1H, J= 1.70 Hz), 7.35-7.26 (m, 2H), 7.25-7.16 (m, 3H),4.82 (t, 1H, J = 5.46 Hz), 3.54 (dd,.2H, J = 5.84, 5.65 Hz), 3.43-3.32 (m, 2H), 2.45-2.35 (m, 1H),2.14-2.04 (m, 1H), 1.57-1.47 (m, 1H), 1.44-1.33 (m, 1H). LCMS: (M+H+) 432.0, (M+Na+) 454.0. HRMS: (M+H+) calcd for CzaH^NsCU, 432.1672, found 432.1648.

Example 171: (1R.2R)- 6-Oxo-8-f(2-phenvl-cvclopropanecarbonvl)-amino1-5,6-dihydro-1H- f 1.21diazepino[4.5,6-cdlindole-2-carboxvlic acid (2-dimethvlamino-ethvl)-amide 25

Title Compoundof Example 165

HN-N

013017 189

Step 1- Préparation of 8-Amino-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; dihydrochloride 171 (a)

Préparation of intermediate 171(a) from the title compound of Example 165 (55.0 mg, 0.133mmol) and 4.0 M HCl in dioxane (0.66 mL) was carried out analogously to Example 91. Isolation, 5 alsO in an analogous manner, afforded Intermediate 171(a) (51.3 mg, 0.132 mmol) as a yellowpowder in 99% yield. LCMS: (M+H+) 315.2.

Step 2. Préparation of Title Compound: (1R,2R)- 6-Oxo-8-[(2-phenyl- cyclopropanecarbonyl)-amino]-5,6-dihydro-1tf-[1,2]diazepino[4,5,6-cd]indole-2-carboxylic 10 acid (2-dimethylamino-ethyl)-amide

Préparation of the title compound from Intermediate 171(a) (51.3 mg, 0.132 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (24.0 mg, 0.148 mmol), triethylamine (0.074 mL, 0.535mmol), and 0-(7-azabenzotriazol-1-yl)-W,W,A/’,/V-tetramethyluronium hexafluorophosphate (76.0mg, 0.200 mmol) in /V,A/-dimethylformamide (2.0 mL) was carried out analogously to Example 11. 15 The reaction mixture was reduced in volume and subjected to préparative HPLC (H1-Q C18reverse-phase 5uM, 10OA, 150x20 column eluting with CH3CN/0.1% acetic acid in H2O at aflowrate of 20 mL/min using a gradient of 20-60% CH3CN over 30 min) to afford the titlecompound (15 mg, 0.0328 mmol) as a yellow-green powder in 25% yield. 1H NMR (ds-DMSO): δ 10.63 (s, 1H), 10.53 (s, 1H), 8.71 (brs, 1H), 8.20 (d, 1H, J= 1.13 Hz), 8.06 20 (s, 1H), 7.70 (d, 1H, J = 0.94 Hz), 7.37-7.26 (m, 2H), 7.26-7.15 (m, 3H), 3.70-3.60 (m, 2H), 3.22- 3.11 (m, 2H), 2.76 (s, 6H), 2.42-2.32 (m, 1H), 2.16-2.04 (m, 1H), 1.58-1.46 (m, 1H), 1.46-1.33 (m,1H). LCMS: (M+H+) 459.1, (M+Na+) 481.1. HRMS: (M+H+) calcd for C25H27N6O3, 459.2145, found 459.2151. 25 Examole 172: (1.2-(rans)-2-(3-MorDholin-4-vlmethvl-phenvl)-cvclopropanecarboxvlic acid (6-oxo- 5.6-dihvdro-1-f1.2ldiazepinof4,5.61indol-8-vh-amide

I

PdOAc>2, EtsNP(Tol)3, DMF, 80 °C

172(b) 013017 190

lEt 172<a)

1. LiOH, THF, H2O 2. HATU, Et3N, DMF,Title Compound ofExample 2 5%

Me3SOT, NaH DMSO, 35%

HN-N

Step 1. Préparation of 3-(3-Morpholin-4-ylmethyl-phenyl)-acrylic acid ethyl ester 172(a) 5 To a solution of4-(3-iodo-benzyl)-morpholine (3.44 g, 11.4 mmol) in A/./V-dimethylformamide (20 mL) was added triethylamine (1.7 mL, 12.5 mmol), ethyl acrylate (4.1 mL, 45.4 mmol), tri-o-tolylphosphine (346 mg, 1.14 mmol) and palladium (II) acetate (127 mg, 0.57 mmol). The mixturewas heated at 80 °C overnight. After concentration,, the mixture was chromatographed on silicagel to afford Intermediate 172(a) as a colorless oil (2.37 g, 9.1 mmol) in 80% yieid. 10 Step 2. Préparation of (1,2-frans)-2-(3-Morpholin-4-ylmethyl-phenyl)-cyclopropanecarboxylic acid ethyl ester 172(b)

Préparation of intermediate 172(b) from Intermediate 172(a) (472 mg, 1.81 mmol), NaH (94 mg,2.35 mmol) and trimethylsulfoxonium iodide (517 mg, 2.35 mmol) was carried out analogously tostep 1 of Example 181. After workup, the residue was purified by silica gel chromatography, 15 eluting with 40% ethylacetate/hexane, to give Intermediate 172(b) as a colorless oil (175 mg, 0.64mmol) in 35 % yieid.

Step 3. Préparation of Title compound (1,2-(rans)-2-(3-Morpholin-4-yimethyl-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cdIindol-8-yl)-amide 20 To a solution of Intermediate 172(b) (175 mg, 0.64 mmol) in tetrahydrofuran (2 mL) was added 1M aqueous LiOH (3.8 mL, 3.8 mmol). The resulting mixture was stirred overnight whereuponmixture was acidified to pH 2 and extracted with ethyl acetate. Concentration of the organic layergave crude 2-(3-morpholin-4-ylmethyl-phenyl)-cyclopropanecarboxylic acid which was combinedwith the title compound from Example 2 (227 mg, 0.756 mmol), triethylamine (0.32 mL, 2.27 25 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,W,W’,W-tetramethyluronium hexafluorophosphate (345mg, 0.907 mmol) in W,/V-dimethylformamide (5 mL). After was stirring ovemight, the volatile 013017 191 components were removed under vacuum, and the residue was purified by silica gelchromatography to give the title compound as yellow solid (15 mg, 0.03 mmol) in 5% yield. 1H NMR (CD3OD): 5 8.30 (s, 1H), 7.59 (s, 1 H), 7.61 (s, 2H), 7.51-7.28 (m, 4H), 3.84 (s, 4H), 3.66(s, 2H), 2.61 (s, 4H), 2.45 (m, 1H), 2.21 (m, 1H), 1.76 (m, 1H), 1.53 (m, 1H). 5 LCMS: (M+H+) 444.2

Example 173: (1,2-frans)-2-[3-(4-Methvl-piperazin-1-vl)-phenvn-cvclopropanecarboxvlic acid (6- □xo-5,6-dihvdro-1 /-/-11 .2ldiazepinoi4,5,6-ccflindol-8-yl')-amide

Intermediate 202(a),Exemple 202 -».

PdOAcfe. BINAPCS2CO3, toluene, 63%

173(a)

22% 10 15 20

Step 1. Préparation of 2-[3-(4-Methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylic acidethyl ester 173(a)

To a solution of Intermediate 202(a) of Example 202 (165 mg, 0.616 mmol) in toluene (4 mL) wasadded 2,2'-bis(diphenylphosphino)-1,T-binaphthyl (34.5 mg, 0.055 mmol), 4-methylpiperazine(0.082 mL, 0.74 mmol), Cs2CO3 (281 mg, 0.862 mmol) and Pd(OAc)2 (8.3 mg, 0.037 mmol). Themixture was refluxed ovemight. The brown mixture was then filtered and the filter cake waswashed with ethyl acetate. After concentrating the filtrate, the residue was purified by silica gelchromatography, eluting with 2-5% MeOH/CH2CI2i to afford Intermediate 173(a) as a colorless oil(111 mg, 0.39 mmol) in 63% yield.

Step 2. Préparation of Titie compound: (1,2-frans)-2-[3-{4-Methyi-piperazin-1-yI)-phenyl]-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yi)-amide

In a manner similar to that described for step 3 of Example 172, Intermediate 173(a) was treatedwith 1 m aqnpniis LiOH to oive crude 2-|3-(4-methyl-piperazin-1-yl)-phenyi]-cyciopropanecarboxylic acid. Crude 2-[3-(4-methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylicacid was coupled to the title compound of Example 2 (71 mg, 0.3 mmol) also in a manner similarto that described for step 3 of Example 172. Extractive work-up from ethyl acetate and saturated 25 013017 192 aqueous NaHCO3 afforded the crude product, which was purified by silica gel chromatography,eluting with 3% MeOH\CH2CI2, to furnish the title compound (38 mg, 0.086 mmol) in 22% yield. ’H NMR (ds-DMSO): δ 11.70 (s, 1H), 10.38 (s, 1H), 10.23 (s, 1H), 8.13 (s, 1H), 7.59 (s, 1H), 7.56(s, 1 H), 7.47 (s, 1 H), 7.13 (m, 1H), 6.79-6.74 (m, 2H), 6.58 (m, 1H), 3.22-3.12 (m, 4H), 2.51-2.47 5 (m, 4H), 2.33 (m, 1 H), 2.27 (s, 3H), 2.08 (m, 1 H), 1.46 (m, 1 H), 1.36 (m, 1 H). LCMS: (M+H+) 443.2

Example 174: (1.2-fra/7s)-2-f3-Morpholin-4-vl-phenvn-cvclopropanecarboxvlic acid (6-oxo-5,6- dihvdro-1 H-l 1.21diazepinof4,5.6-cdlindol-8-vD-amide

Intermediate 202(a),Example 202

PdOAc)2, BINAPCS2CO3, toluene, 34%

174(a)

27% 10

Step 1. Préparation of 2-[3-Morpholin-4-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester174(a)

Préparation of intermediate 174(a) from Intermediate 202(a) of Example 202 (239 mg, 0.892 15 mmol), 2,2'-bis(diphenylphosphino)-1,r-binaphthyl (50 mg, 0.081 mmol), morpholine (0.12 mL,1.34 mmol), Cs2CO3 (407 mg, 1.25 mmol) and Pd(OAc)2 (12 mg, 0.054 mmol) in toluene (5 mL)was carried analogously to Example 173. After concentration, the residue was purified by silica gelchromatography, eluting with 1-2 % MeOH/CH2CI2 to afford Intermediate 174(a) as a colorless oil(84 mg, 0.31 mmol) in 34% yield: 20 Step 2. Préparation of Title compound: (1,2-frans)-2-(3-Morpholin-4-yl-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,S,6-cd]indol-8-yl)- amide

Préparation of the title compound was carried out analogously to step 3 of Example 172 exceptthat Intermediate 174(3) was used inetead of Intermediate 179(h) The title nnmpnund was 25 obtained in 27% yield. 1H NMR (d6-DMSO): δ 10.37 (d, 1H, J = 2.26 Hz), 10.24 (s, 1H), 8.24 (d, 1H, J = 1.88 Hz), 7.58 (d,1H, J = 1.51 Hz), 7.56 (d, 1H, J = 3.30 Hz), 7.47 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.79-6.77 (m, 013017 193 2H), 6.61 (d, 1H, J= 8.0 Hz), 3.74-3.72 (m, 4H), 2.23 (m, 1H), 2.07 (m, 1H), 1.46 (m, 1H), 1.38(m,1H). LCMS: (M+H+) 430.2

Example_175._(2R)-2-Amino-2-f4-hvdroxvphenvl)-/V-(6-oxo-2-phenvl-5.6-dihvdro-1H- 5 11,21diazepinol4,5.6-ccflindol-8-yl)ethanamide hvdrochloride

Préparation of example 175 from the title compound of Example 153 (38 mg, 0.072 mmol) and4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, included freebasing with triethylamine and subséquent silica gel 10 chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purifiedfreebase in CH2CI2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of thevolatile eomponents, the title compound (20 mg, 0.043 mmol) was obtained as an orange/yellowpowder in 60% yield. ’H NMR (ds-DMSO): δ 12.23 (s, 1H), 10.82 (s, 1H), 10.45 (s, 1H), 8.71 (brs, 3H), 8.10 (s, 1H), 15 7.75-7.65 (m, 3H), 7.63-7.49 (m, 4H), 7.43 (d, 2H, J = 8.47 Hz), 6,86 (d, 2H, J = 8.47 Hz), 5.02 (m, 1H). LCMS: (M+H+) 426.2.

Example 176:_(2ffl-2-Amino-3-naphthalen-2-vl-/V-f6-oxo-2-phenvl-5.6-dihvdro-1H- H ,21diazepinOi4.5,6-cdlindol-8-vl)propanamide hvdrochloride

Préparation of example 176 from the title compound of Example 154 (59 mg, 0.103 mmol) and4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner afforded the title compound (52 mg, 0.102 mmol) as an orange/yellow powderin 99% yield. 25 1H NMR (d6-DMSO): δ 12.24 (s, 1H), 10.82 (s, 1H), 10.44 (s, 1H), 8.43 (br s, 3H), 8.07 (s, 1H),7.93-7.81 (m, 5H), 7.71-7.45 (m, 9H), 4.32 (br s, 1H), 3.44 (m, 1H, partially obscured), 3.28 (m,1H). LCMS: (M+H+) 474.2, (M+Na+) 496.3. 013017 194

Example 177: (2/?)-2-Amino-/V-(6-oxo-5,6-dihvdro-1H-ri,2ldiazepinof4,5.6-ccnindol-8-vl)-3- iïphenylmethvOoxvIpropanamide hvdrochloride

Préparation of example 177 from the title compound of Example 159 (35 mg, 0.072 mmol) and5 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner afforded the title compound (30 mg, 0.072 mmol) as an orange/yellow powder in 100% yield. 1H NMR (ds-DMSO): δ 11.89 (s, 1H), 10.75 (s, 1H), 10.32 (s, 1H), 8.45 (br s, 3H), 8.06 (s, 1H),7.63 (s, 2H), 7.50 (s, 1H), 7.38-7.26 (m, 5H), 4.59 (dd, 2H, J= 12.25, 17.33 Hz), 4.24 (brs, 1H), 10 3.89 (d, 2H, J = 4.15 Hz, partially obscured). LCMS: (M+H+) 378.2, (M+Na+) 400.1.

Example 178: (2R)-2-Amino-3-(4-hydroxvphenvl)-/V-(6-oxo-5,6-dihydro-1 H-Π .2)diazepino[4.5.6- cd|indol-8-vl)propanamide hvdrochloride

15 Préparation of example 178 from the title compound of Example 155 (90 mg, 0.194 mmol) and4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner afforded the title compound (56 mg, 0.140 mmol) as an orange/yellow powderin 72% yield. 1H NMR (d6-DMSO): δ 11.89 (s, 1H), 10.70 (s, 1H), 10.30 (s, 1H), 9.38 (brs, 1H), 8.34 (brs, 3H), 20 8.03 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.08 (d, 2H, J = 8.29 Hz), 6.70 (d, 2H, J = 8.29 Hz), 4.11 (br s, 1H), 2.93-3.15 (m, 2H). LCMS:(M+Na+) 386.5, (M-H)' 362.4.

Example 179: (2R)-2-Amino-3-naphthalen-2-vl-A/-(6-oxo-5.6-dihvdro-1 H-H ,21diazepinof4,5.6- ccflindol-8-vQpropanamide hvdrochloride

25 013017 195 10 15 20

Préparation of example 179 from the title compound of Example 158 (57 mg, 0.115 mmol) and4M HCl in dioxane (10 mL) was càrried out analogously to Example 91. Isolation, also in ananalogous manner afforded the title compound (48 mg, 0.111 mmol) as an orange/yellow powderin 97% yield. 1H NMR (d6-DMSO): δ 11.88 (s, 1H), 10.82 (s, 1H), 10.30 (s, 1H), 8.43 (brs, 3H), 8.04 (s, 1H),7.93-7.78 (m, 4H), 7.64-7.57 (m, 2H), 7.54-7.45 (m, 4H), 4.32 (br s, 1H), 3.22-3.46 (m, 2H,partially obscured). LCMS: (M+H+) 398.5, (M+Na+) 420.4.

Example 180: 2-(1,1 '-Biphenvl-4-vl)-A/-(6-oxo-5,6-dihydro-1 H-l 1.21diazepinof4.5.6-ct/lindol-8- vDacetamide

Préparation of example 180 from the title compound of Example 2 (75 mg, 0.38 mmol), 1,1'-biphenyl-4-ylacetic acid (93 mg, 0.44 mmol), triethylamine (0.16 mL, 1.15 mmol), and O-(7-azabenzotriazol-1-yl)-W,W,N’,/V’-tetramethyluronium hexafluorophosphate (167 mg, 0.44mmol) inCH2CI2 (1.0 mL) and A/,/V-dimethylfomnamide (1.0 mL) was carried out analogously to Example11 Silica gel chromatography was performed twice eluting both times with 1:1 hexane:acetoneand the purest fractions were combined, evaporated, and the resulting solids triturated withmethanol to afford the title compound (5 mg, 0.012mmol) as a yellow powder in 3% yield. 1H NMR (de-DMSO): § 11.74 (s, 1H), 10.35 (s, 1H), 10.25 (s, 1H), 8.14 (s, 1H), 7.69-7.54 (m, 6H),7.51-7.33 (m, 6H), 3.69 (s, 2H). LCMS: (M+H+) 395.4, (M+Na+) 417.4.

Example 181: (1.2-frans)-2-(4-Hvdroxv-phenvl)-cvclopropanecarboxylic acid (6-oxo-5.6-dihvdro- 1W-F1 .21diazepinor4,5,6-ccflindol-B-vl)-amide 013017 196

BBr3, CH2CI2,25% 181(a) CO2Et

1M LiOH, THF, H2O 97% HO·

181(c)

CO2H 181(b)

Title Compoundof Example 2

H

°i:syN~N

HATU, EI3N, DMF, 16%

Step 1. Préparation of (1,2-frans)-2-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid ethylester 181 (a)

To a mixture of NaH (200 mg, 5.0 mmol) and trimethylsulfoxonium iodide (1.1 g, 5.0 mmol) was5 added DMSO (10 mL). After stirring for 30 min, a solution of 3-(4-methoxy-phenyl)-acrylic acidethyl ester (400mg, 1.92 mmol) in DMSO (5 mL) was added drop-wise. After stirring overnight, themixture was partitioned between ethyl acetate and water. The aqueous layer was re-extractedwith ethyl acetate, and the combined organic layers were dried over Na2SO4 and concentrated.

Purification by silica gel chromatography eluting with 10 % ethyl acetate in hexane gave 10 Intermediate 181(a) (318 mg, 1.44 mmol) in 72%yield.

Step 2. Préparation of (1,2-?rans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethylester 181(b)

To a stirred solution of Intermediate 181(a) (318 mg, 1.45 mmol) in CH2CI2 (8 mL) at -78 °C wasadded 1M BBr3 in CH2CI2 (1.7 mL). The resulting mixture was then warmed to 23 °C and stirred 15 for 30 min. The mixture was quenched with saturated aqueous NaHCO3 and extracted withCH2CI2. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, andsubjected to silica gel chromatography eluting with 15% ethyl acetate in hexane to affordIntermediate 181 (b) as a colorless oil (75 mg, 0.364 mmol) in 25% yield.

Step 3. Préparation of (1,2-irans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxyIic acid 181(c) 20 To a stirred solution of Intermediate 181 (b) (75mg, 0.36 mmol) in tetrahydrofuran (2.5 mL) wasadded aqueous 1M LiOH (2.5 mL). The resulting mixture was stirred at 23 °C for 12 hours. Themixture was then acidified with 1M HCl to pH 1 and extracted with ethyl acetate. The organic layerwas then washed with brine and concentrated to give Intermediate 181(c) (63 mg, 0.35 mmol) in97% yield which was carried on without further purification. 013017 197

Step 4. Préparation of Title Compound: (1,2-irans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxy lie acid (6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide

Préparation of the title compound from the title compound of Example 2 (66 mg, 0.278 mmol),Intermediate 181(c) (62 mg, 0.348 mmol), triethylamine (0.073 mL, 0.52 mmol), and O-(7-azabenzotriazol-1-yl)-W,A/,W’,W'-tetramethyluronium hexafluorophosphate (159 mg, 0.42 mmol) inΛ/,/V-dimethylformamide (2 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 2% methanol in CH2CI2), aiso in an analogous manner, afforded thetitle compound (20 mg, 0.056 mmol) as a yellow powder in 16% yield. 1H NMR (d6-DMSO): 12.09 (s, 1H), 10.38 (s, 1H), 10.37 (s, 1H), 9.26 (br s, 1H), 8.16 (s, 1H),7.65-7.67 (m, 2H), 7.58 (t, J - 8.0 Hz, 1H), 7.50 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.0Hz, 2H), 2.33 (m, 1 H), 1.98 (m, 1 H), 1.43 (m, 1 H), 1.24 (m, 1 H). LCMS: (M+Hj 361.3.

Example 182: (1,2-frans)-2-(4-Hvdroxv-phenvl)-cvclopropanecarboxvlic acid (6-oxo-2-phenvl-5.6- dihvdro-1-f1.21diazepinof4,5,6lindol-8-vli-amide

Préparation of example 182 from the title compound of Example 7 (35 mg, 0.127 mmol),Intermediate 181(c) of Example 181 (66 mg, 0.372 mmol), triethylamine (0.062 mL, 0.45 mmol),and O-(7-azabenzotriazol-1-yl)-/V,W,A/',/V-tetramethyluronium hexafluorophosphate (156 mg, 0.41mmol) in ty/V-dimethylformamide (3 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 2% methanol in CH2CI2), also in an analogous manner, gave the titlecompound (32 mg, 0.073 mmol) as a yellow powder in 20% yield. 1H NMR (dr methanol): 8.04 (s, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 6.91 (d, J = 9.0 Hz,2H), 6.62 (d, J= 9.0 Hz, 2H), 2.31 (m, 1H), 1.87 (m, 1H), 1.43 (m, 1H), 1.24 (m, 1H). LCMS: (M+Hj 437.4.

Example 183: f2-Ethvl-6-oxo-5.6-dihvdro-1B-ri,2(diazepinof4.5.6-ctflindol-8-yl)-carbamic acid tert- butvl ester nue Cempeund PdZC. Ho. DMF. MeOHof Example 164 - 69%

BocHN

HN-N jet'

Palladium (10% on activated carbon) (0.23 g, 0.198 mmol) was added to a solution of the titlecompound of Example 164 (0.65 g, 1.99 mmol) in 1:10 W,A/-dimethylformamide: methanol (11 013017 b"CKX ΠΙΨ Intermediate 147(d)Example 147 \ JU Pd(dppf)CI2,2 M Na2CO3 DMF, 80 °C, 94% RocHN''^-^

Under an argon atmosphère, 2.0 M aqueous Na2CO3 (0.66 mL) wasIntermediate 147(d) of Example 147 (100 mg, 0.265 mmol), 198 mL). The reaction mixture was purged with H2 and stirred at room température under H2 (1 atm.)for 5 hours. The palladium was filtered and the volatile components were removed in vacuo. Theresulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was thenloaded onto a silica gel column and eiuted with 1.2:1 dichloromethane: ethyl acetate to afford the 5 title compound (0.45 g, 1.37 mmol) as a yellow solid in 69% yield. 1H NMR (de-DMSO): δ 11.54 (s, 1H), 10.05 (s, 1H), 9.37 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.44(s, 1 H), 2.80 (dd, 2H, J = 7.35, 7.54 Hz), 1.48 (s, 9H), 1.23 (t, 3H, J = 7.54 Hz). LCMS: (M+H+) 329.5, (M+Na+) 351.5; (M-H)'327.4.

Example 184: 4-(8-fert-Butoxvcarbonvlamino-6-oxo-5.6-dihvdro-1H-[1,21diazepinof4,5,6-cdlindol- 10 2-vl)-3.6-dihvdro-2H-pvridine-1-carboxvlic acid ferf-butvl ester

-N ?—G NBoc

''N fH added to a mixture of4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2/7-pyridine-1-carboxylic acid fert-butyl ester (122 mg, 0.39515 mmol) and [1,T- bis(diphenylphosphino)ferTocene]dichloropalladium (II) (10.8 mg, 0.013 mmol) inanhydrous A/.W-dimethylformamide (5 ml). The mixture was heated at 80 °C for 16 hours. Thereaction was filtered through a thin pack of diatomaceous earth, and the volatile components wereremoved in vacuo. Silica gel chromatography (eiuted with 1:1 ethyl acetate: hexane) afforded the title compound (120 mg, 0.249 mmol) as a yellow powder in 94% yield. 20 1H NMR (d6-DMSO): δ 11.62 (s, 1H), 10.22 (s, 1H), 9.46 (s, 1H), 7.69 (s, 1H), 7.65 (d, 1H, J = 1.70 Hz), 7.49 (s, 1H), 6.16 (s, 1H), 4.06 (s, 2H), 3.56 (t, 2H, J = 5.65, 4.90 Hz), 3.31 (m, 2H,partially obscured), 1.49 (s, 9H), 1.44 (s, 9H). LCMS: (M+H+) 482.5, (M+Na+) 504.5; (M-H)' 480.5. HRMS: (M+H4) calcd for C25H32N5O5, 482.2403, found 482.2417. 25 The 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester starting material was prepared according to Eastwood, P.R. (2000) TetrahedronLetters 41(19):3705-3708 from trifluoromethanesulfonic acid 1-ferf-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl ester which in tum was prepared according to the procedure outlined byBarrow, J. C. et. al.(2000) J. Med. Chem. 43(14) 2703-2718. 013017 199

Example 185: 8-Amtno-2-(1,2,3,6-tetrahydro-pvridin-4-vl)-1.5-dihvdro-î1.21diazepinol4.5.6- ctflindol-6-one

10

Préparation of example 185 from the title compound of Example 184 (20 mg, 0.042 mmol) and4.0 M HCl in dioxane (0.1 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, afforded the title compound (14.7 mg, 0.042 mmol) as a yellow powder in99% yield. ’H NMR (de-DMSO): δ 12.20 (br s, 1H), 10.46 (s, 1H), 9.14 (s, 3H), 7.57 (s, 1H), 7.36 (s, 2H), 6.22(s, 1H), 3.83 (s, 2H), 3.36 (s, 2H), 2.74 (s, 2H). LCMS: (M+Na+) 304.3; (M-H)’ 280.2. HRMS: (M+H+) calcd for C1SH1SN5O, 282.1355, found 282.1349.

Example 186: (1R.2R)- 2-Phenvl-cvclopropanecarboxvlic acid (2-ethvl-6-oxo-5.6-dihvdro-1H- f1.2ldiazepinof4.5,6-ccnindol-8-v0-amide

15

Step 1. Préparation of 8-Amino-2-ethyl-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one(hydrochloric sait) 186(a)

Préparation of intermediate 186(a) from the title compound of Example 183 (120 mg, 0.366 mmol)and 4.0 M HCl in dioxane (0.92 mL) was carried out analogously to Example 91. Isolation, also inan analogous manner, afforded Intermediate 186(a) (95.5 mg, 0.366 mmol) as a yellow powder in99% yield. LCMS: (M-uH+) 99Q 1 20 013017 200 10 15

Step 2. Préparation of Title Compound: (1 R,2R)-2-Phenyl-cyclopropanecarboxyiic acid (2-ethyl-6-oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cdJindol-8-yl)-amide

Préparation of the title compound from Intermediate 186(a) (95.5 mg, 0.366 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (65.0 mg, 0.401 mmol), triethylamine (0.510 mL, 3.66 mmol),and 0-(7-azabenzotriazol-1-yl)-A/,/\/,/\/',W-tetramethyluronium hexafluorophosphate (210 mg,0.552 mmol) in A/,W-dimethylformamide (4.0 mL) was carried out analogously to Example 11. Thevolatile components were removed in vacuo and the resulting residue was dissolved in methanoland loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and elutedwith 1.2:1 dichloromethane: ethyl acetate to afford the title compound (80 mg, 0.215 mmol) as ayellow solid in 59% yield. TH NMR (ds-DMSO): δ 11.63 (s, 1H), 10.31 (s, 1H), 10.09 (s, 1H), 8.00 (d, 1H, J = 1.51 Hz), 7.52(d, 1H, J= 1.51 Hz), 7.45 (s, 1H), 7.34-7.24 (m, 2H), 7.24-7.13 (m, 3H), 2.81 (q, 2H, J = 7.54 Hz),2.41-2.31 (m, 1H), 2.11-2.00 (m, 1H), 1.53-1.43 (m, 1H), 1.40-1.29 (m, 1H), 1.23 (t, 3H, J = 7.54Hz). LCMS: (M+H+) 373.1. HRMS: (M+H+) calcd for C22H21N4O2, 371.1665, found 373.1672.

Example 187: i2-Chloro-6-oxo-5.6-dihvdro-1H-f1.21diazepinor4.5.6-cdlindol-8-vh-carbamic acid tert-butvl ester 20

Intermediate 1471c),Example 147 NCS, DMF50 °C, 90% HN-NOs-/ \\

BocHN

W-Chlorosuccinimide (0.47 g, 3.52 mmol) was added to a solution of Intermediate 147(c) ofExample 147 (1.00 g, 3.33 mmol) in anhydrous Λ/,/V-dirnethylformamide (10 ml) and anhydrouschloroform (6.5 mL). The reaction was heated at 50 °C for 3 hours at which point the volatilecomponents were removed in vacuo. The resulting residue was dissolved in methanol and loadedonto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 23:2:50dichloromethane: methanol: ethyl acetate to afford the title compound (1 g, 2.99 mmol) as ayellow solid in 90% yield. NMR (d6-DMSO): δ 12.52 (s, 1H), 10.41 (s, 1H), 9.51 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.32(s, 1H), 1.47 (s, 9H). LCMS: (M+H+) 335.1, (M+Na+) 357.0; (M-H)’333.0. 25 013017 201

Example 188: (1,2-frans)-2-Pyridin-3-yl-cvclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihvdro- 1 H-11,21diazepinof4.5,6-cdlindol-8-vl)-amide

10 15 20

Préparation of example 188 from Intermediate 186(a) of Example 186 (90 mg, 0.341 mmol),crude (1,2-fnans)-2-pyridin-3-yl-cyclopropanecarboxylic acid (see Example 125 for preparation-estimated purity e.a. 75%) (79.5 mg, c.a. 0.341 mmol), triethylamine (0.237 mL, 1.73 mmol), andO-(7-azabenzotriazoH-yl)-/V,/V,/V’,A/-tetramethyluronium hexafluorophosphate (194 mg, 0.510mmol) in W,W-dimethylformamide (4.0 mL) was carried out analogously to Example 11. Thevolatile components were removed in vacuo, and the resulting residue was dissolved in methanoland loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and elutedwith 50:3 dichloromethane: methanol to afford the title compound (75 mg, 0.201 mmol) as ayellow solid in 59% yield. 1H NMR (ds-DMSO): δ 11.65 (s, 1H), 10.36 (s, 1H), 10.11 (s, 1H), 8.51 (d, 1H, J= 1.88 Hz), 8.42(dd, 1 H, J = 1.32,1.32 Hz), 8.01 (d, 1 H, J = 1.70 Hz), 7.57 (dt, 1H, J = 7.91, 1.88 Hz), 7.53 (d, 1H,J = 1.70 Hz), 7.47 (s, 1H), 7.33 (dd, 1H, J = 4.90, 4.71 Hz), 2.82 (q, 2H, J = 7.54 Hz), 2.47-2.38(m, 1H), 2.17-2.08 (m, 1H), 1.58-1.49 (m, 1H), 1.49-1.39 (m, 1H), 1.24 (t, 3H, J = 7.54 Hz). LCMS: (M+H+) 374.2, (M+Na*) 396.0; (M-H)' 372.0. HRMS: (M+H+) calcd for C2iH2oN502, 374.1617, found 374.1620.

Example 189: (R)- 2-Amino-2-cyclohexyl-A/-(2-ethvl-6-oxo-5,6-dihvdro-1H-f1,2ldiazepinof4,5.6- cdlindol-8-vl)-acetamide (hvdrochloride sait)

Intermediate 186(a)Example 186

4N HCl (Dioxane)-:-.-> CH2Ct2,64%

H 013017 202

Step 1. Préparation of (R)-[Cyclohexyl-(2-ethyl-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamoyl)-methyl]-carbamic acid iert-butyl ester 189(a)

Préparation of intermediate 189(a) from Intermediate 186(a) of Example 186 (90 mg, 0.341mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (88 mg, 0.342 mmol), triethylamine(0.237 mL, 1.73 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,W’,W’-tetramethyluroniumhexafluorophosphate (194 mg, 0.510 mmol) in W,/V-dimethylformamide (4.0 mL) was carried outanalogously to Example 11. The volatile components were removed in vacuo, and the resultingresidue was dissolved in methanol and ioaded onto a silica gel plug. The plug was then ioadedonto a silica gel column and eluted with 1.2:1 dichloromethane: ethyl acetate to affordIntermediate 189(a) (146 mg, 0.313 mmol) as a yellow solid in 91% yield. 1H NMR (d6-DMSO): δ 11.64 (s, 1H), 10.12 (s, 1H), 10.02 (s, 1H), 7.99 (s, 1H), 7.54 (s, 1H), 7.47(s, 1H), 6.87 (d, 1H, J = 7.72 Hz), 3.92 (t, 1H, J = 8.48 Hz), 2.82 (q, 2H, J = 7.54 Hz), 1.78-1.46(m, 6H), 1.38 (s, 9H), 1.24 (t, 3H, J = 7.54 Hz), 1.19-0.94 (m, 5H). LCMS: (M+H+) 468.2, (M+Na+) 490.2.

Step 2. Préparation of Tîtle Compound: (R)- 2-Amino-2-cyclohexyl-W-(2-ethyl-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide (hydrochloric sait)

Préparation of the title compound from Intermediate 189(a) (136 mg, 0.291 mmol) and 4.0 M HClin dioxane (1.5 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (75 mg, 0.186 mmol) as a yellow powder in 64% yield. 1H NMR (d6-DMSO): δ 11.81 (s, 1H), 10.66 (s, 1H), 10.19 (s, 1H), 8.42-8.20 (m, 3H), 7.98 (s, 1H),7.59 (s, 1H), 7.50 (s, 1H), 3.82-3.66 (m, 1H), 2.84 (q, 2H, J = 7.54 Hz), 1.94-1.53 (m, 6H), 1.30-0.98 (m, 8H). LCMS: (M+H+) 368.1, (M+Na+) 390.2; (M-H)' 366.1. HRMS: (M+H+) calcd for C2oH26N502, 368.2087, found 368.2084.

Example 190: (1R.2R)- 2-Phenvl-cyclopropanecarboxvlic acid (2-chloro-6-oxo-5,6-dihvdro-1H- [1,2ldiazepinof4,5,6-cdlindol-8-vl)-amide

Title Compoundof Example 187

DMF, 45%

HN—N

013017 203

Step 1. Préparation of 8-Amino-2-chloro-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one(hydrochloric sait) 190(a)

Préparation of intermediate 190(a) from the title compound of Example 187 (0.83 g, 2.48 mmol)and 4.0 M HCl in dioxane (6.2 mL) was carried out analogously to Example 91. Isolation, also inan analogous manner, afforded Intermediate 190(a) (0.66 g, 2.44 mmol) as a yellow powder in98% yield. ’H NMR (de-DMSO): δ 12.87 (s, 1H), 10.57 (s, 1H), 7.38 (s, 2H), 7.27 (s, 1H). LCMS: (M-H)‘233.1.

Step 2. Préparation of Title Compound: (1 R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-chloro-6-oxo-5,6-dihydro-1 H-{1,2]diazepino[4,5,6-cd]indol-8-yl)-amtde

Intermediate 190(a) (120 mg, 0.443 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (86.0mg, 0.531 mmol), (3-dimethylamino-propyI)-ethyl-carbodiimide hydrochloride (102 mg, 0.534mmol), and 4-dimethylaminopyridine (65 mg, 0.533 mmol) were stirred in W,W-dimethylformamide(7.0 mL) at room température for 16 h at which point the volatile components were removed invacuo. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. Theplug was then loaded onto a silica gel column and eluted with 1.2:1 dichloromethane: ethylacetate to afford the title compound (75 mg, 2.99 mmol) as a yellow solid in 45% yield. ’H NMR (de-DMSO): δ 12.65 (s, 1H), 10.46 (s, 2H), 8.09 (s, 1H), 7.63 (s, 1H), 7.36 (s, 1H), 7.34-7.25 (m, 2H), 7.25-7.12 (m, 3H), 2.44-2.30 (m, 1H), 2.13-2.01 (m, 1H), 1.57-1.44 (m, 1H), 1.44-1.31 (m, 1H). LCMS: (Μ-H)'377.1. HRMS: (M+H+) calcd for C20HWN4O2CI, 379.0962, found 379.0941.

Example 191: f1.2-trans)-2-Pvridin-3-vl-cvclopropanecarboxvlic acid (2-chloro-6-oxo-5,6-dihvdro- 1H-H.21diazepinor4.5.6-cdlindol-8-vl)-amide

Préparation of example 191 from Intermediate 190(a) of Example 190 (120 mg, 0.443 mmol),crude 2-pyridin-3-yl-cyclopropanecarboxylic acid (estimated purity c.a. 75%) (124 mg, c.a. 0.532mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.534 mmol), and 4-dimethylaminopyridine (65 mg, 0.533 mmol) in /V,/V-dimethylformamide (7.0 mL) was carried outanalogously to Example 190, Step 2. When the reaction was judged complété, the volatilecomponents were removed in vacuo, and the resulting residue was dissolved in methanol andloaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 013017 204 10 15 20 50:3 dichloromethane: methanôl to afford the title compound (80 mg, 0.210 mmol) as a yellowsolid in 48% yield. 1H NMR (de-DMSO): δ 12.65 (s, 1H), 10.48 (s, 1H), 10.46 (s, 1 H), 8.51 (s, 1H), 8.42 (d, 1H, J =3.20 Hz), 8.09 (d, 1H, J= 1.13 Hz), 7.63 (d, 1H, J= 1.32 Hz), 7.57 (d, 1H, J = 7.91 Hz), 7.40-7.28(m, 2H), 2.47-2.37 (m, 1H), 2.19-2.06 (m, 1H), 1.60-1.50 (m, 1 H), 1.50-1.40 (m, 1H). .LCMS: (M+H+) 380.0, (M+Na+) 402.1; (M-H)’378.0. HRMS: (M+H+) calcd for C19H1SNSO2CI, 380.0914, found 380.0922.

Example 192: /V-(6-oxo-5.6-dihvdro-1H-f1.21diazepinor4,5.6-cdlindol-8-vl)-N*-fph'erivlmethvl)urea

Title Compundof Example 2

HN-N

DSC, EtN(iPr)2, DMF25%

To the title compound of Example 2 (45 mg, 0.19 mmol) and W,W’-disuccinimidyl carbonate (49mg, 0.19 mmol) was added /V,W-dimethylformamide (0.5mL) and triethylamine (0.084 mL, 0.60mmol). After 3 to 5 min, benzylamine (0.046 mL, 0.20 mmol) was added, and the reaction wasstirred for about an hour. Methylene chloride.methanol (4:1) was added and the resulting solidswere removed by trituration. The triturate was loaded onto a silica gel plug and evaporated. Theplug was then loaded onto a silica gel column and eluted with hexane:acetone (1:1) and thepurest fractions were combined. After solvent removal, the title compound (16 mg, 0.048 mmol)was obtained as brown powder in 25% yield. 'H NMR (d6-DMSO): δ 11.61 (s, 1H, exchanges), 10.19 (s, 1H, exchanges), 8.75 (s, 1H,exchanges), 7.93 (s, 1H), 7.49 (m, 1H), 7.40-7.30 (m, 7H), 6.55 (m, 1H, exchanges), 4.31 (d, 2H,J = 5.84 Hz). LCMS: (M+H+) 334.2, (M+Na+) 356.3

Example_193:_(2R)-3-i4-Hvdroxvphenvl’)-2-(methvlaminoi-ZV-(6-oxo-5.6-dihvdro-1/-/- [1.21diazepinof4.5.6-cdlindol-8-vl)propanamide hvdrochloride

Préparation of example 193 from the title compound of Example 156 (121 mg, 0.25 mmol) and4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner, afforded the title compound (74 mg, 0.18 mmol) as an orange/yellow powderin 72% yield. 25 013017 205 1H NMR (d6-DMS0): major component/conformer; δ 11.89 (s, 1H, exchanges), 10.73 (s, 1H,exchanges), 10.31 (s, 1 H, exchanges), 9.36 (br s, 2H, exchanges), 9.11 (br s, 1H, exchanges),7.99 (s, 1H), 7.64 (s, 1 H), 7.56 (s, 1H), 7.50 (s, 1H), 7.06 (d, 2H, J = 8.48 Hz), 6.69 (d, 2H, J =8.48 Hz), 4.11 (m, 1H), 3.18 (m, 1 H), 3.08 (m, 1H), 2.55 (s, 3H, partially obscurred). LCMS: (M+H+) 378.0, (M+Na+) 400.1.

Example 194: (2RI-2-Amino-3-(4-fluorophenvn-IV-(6-oxo-5,6-dihvdro-1 H-f 1.21diazeDinof4.5.6- ccnindol-8-yOpropanamide hvdrochloride

Préparation of example 194 from the title compound of Example 157 (48 mg, 0.10 mmol) and 4MHCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in ananalogous manner afforded the title compound (34 mg, 0.08 mmol) as an orange/yellow powderin 80% yield. ’H NMR (d6-DMSO): δ 11.88 (s, 1H, exchanges), 10.72 (s, 1H, exchanges), 10.32 (s, 1H,exchanges), 8.37 (br s, 4H, exchanges), 8.04 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.50 (s, 1H),7.38-7.29 (m, 2H), 7.22-7.14 (m, 2H), 4.19 (m, 1H), 3.26-3.03 (m, 2H). LCMS: (M+H*) 366.0, (M+Na+) 388.1.

Example_195:_A/-(6-Oxo-5.6-dihvdro-1 tf-PI .21diazepinoF4.5.6-cd|indol-8-vD-2-(3H- F1.2.31triazolof4,5-bFpvridin-3-vloxv)acetamide

In a manner analogous to that of Example 19, to a stirred suspension of 8-amino-1,5-dihydro-6/-/- [1,2]diazepino[4,5,6-cd] indol-6-one hydrochloride in anhydrous /V,W-dimethylforrnarnide (9 mL)was added bromoacetic acid (168 mg. 1.2 mmol), O-(7-azabenzotriazol-1-yl)-/V,A/,/V',/V-tetramethyluronium hexafluorophosphate (553 mg, 1.4 mmol) and triethylamine.The reaction wasstirred at room température for 16 hours. The volatile components were evaporated and waterwas added to the residue. The precipitated orange solids were collected by filtration and washedwith water and ethyl acetate. After drying, the title compound (158 mg) was obtained as anorange powder in 35% yield. 1H NMR (DMSO -d6) d: 5.28 (1H, s), 7.47 (1H, s), 7.58 (3H, m), 8.09 (1H, d, J = 1.77 Hz), 8.63(1 H, dd, J = 8.59 Hz), 8.83 (1 H, dd, J = 4.55 Hz), 10.27 (1 H, s), 10.52 (1 H, s), 11.77 (1 H, s). LCMS: (M+H*) 377. 013017 206 10 15

Example 196: (1,2-trans)-2-(3-Methoxv-phenvl)-cvclopropanecarboxylic acid (6-oxo-5,6-dihvdro- 1rt-[1.21diazepinof4,5,6-cc/lindol-8-vl)-amide

MeO'

M^SOV, NaH :O2Et DMSO, 43%

186(a)

1. LiOH, THF, H2O 2. HATU, EtgN, DMF,Title Compound ofExample 2 9%

Step 1: Préparation of (1,2-trans)-2-(3-Methoxy-phenyl)-cyclopropanecarboxylic acid ethylester 196(a)

Préparation of intermediate 196(a) from NaH (1.04 g, 26 mmol) and trimethylsulfoxonium iodide(5.72 g, 26 mmol), 3-(methoxy-phenyl)-acrylic acid ethyl ester (4.12 g, 20 mmol) in DMSO (30 mL)was carried out analogously to step 2 of Example 113 to afford Intermediate 196(a) (1.89 g, 8.6mmol) in 43% yield.

Step 2: Préparation of Title compound: (1,2-trans)-2-(3-Methoxy-phenyl)- cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1-[1,2]diazepino[4,5,6-]indol-8-yl)-amide

Préparation of the title compound was camed out analogously to step 3 of Examplé 172 exceptthat Intermediate 196(a) was used instead of Intermediate 172(b). The title compound wasobtained in 9% yield. 1H NMR (de-DMSO): δ 11.85 (d, 1H, J = 2.26 Hz), 10.37 (s, 1H), 10.23 (s, 1H), 8.12 (s, 1H), 7.57(dd, 1H, J = 3.20, 1.51 Hz), 7.46 (s, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.77-6.74 (m, 3H), 3.75 (s, 3H),2.36 (m, 1H), 2.08 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H). LCMS: (M+H+) 375.1.

Example 197: 4-Acetvlamino-A/-(6-oxo-5,6-dihvdro-1H-f1,2idiazepino|4.5,6-cdlindol-8-vl)- benzamide

HN-N

H 20 i 013017 207

Préparation of example 197 from the title compound of Example 2 (124 mg, 0.525 mmol), 4-acetylamino-benzoic acid (113 mg, 0.631 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimidehydrochloride (120 mg, 0.628 mmol), and 4-dimethylaminopyridine (77 mg, 0.631 mmol) in N,N-dimethylformamide (7.0 mL) was carried out analogously to Example 190, Step 2. When the 5 reaction was judged complété, the volatile components were evaporated and methanol wasadded. The mixture was filtered to collect the solids, which were then washed with methanol,dichloromethane and diethyl ether. After drying, the title compound (32 mg, 0.0886 mmol) wasobtained as a yellow powder in 17% yield. 1H NMR (de-DMSO): δ 11.79 (d, 1H, J = 2.64 Hz), 10.25 (s, 1H), 10.23 (s, 2H), 8.27 (d, 1H, J =10 1.70 Hz), 7.96 (d, 2H, J = 8.67 Hz), 7.85 (d, 1H, J = 1.70 Hz), 7.70 (d, 2H, J = 8.67 Hz), 7.58 (d, 1 H, J = 2.64 Hz), 7.48 (s, 1 H), 2.09 (s, 3H). LCMS: (Μ-H)'360.2. HRMS: (M+H+) calcd for C19H16N5O3, 362.1253, found 362.1280.

Example 198: (R)- 2-Amino-/V-(2-chloro-6-oxo-5.6-dihvdro-1H-ff.21diazepinof4,5,6-ccflindol-8-vl)- 15 2-cyclohexvl-acetamide (hvdrochloric sait)

Intermediate 190( a), _NHBoc_

ExampteWO EDCI, Et3N,4-DMAP DMF, 46%

HN—N

198(a) 4N HCl (Dioxane) I --► CH2CI2, 99%

20

Step 1. Préparation of [(2-Chloro-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamoyl)-cyclohexyl-methyl]-carbamic acid fert-butyl ester 198(a)

Préparation of intermediate 198(a) from Intermediate 190(a) of Example 190 (100 mg, 0.369mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (114 mg, 0.443 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (85 mg, 0.445 mmol), and 4-dimethylaminopyridine (54 mg, 0.443 mmol) in W,W-dimethylformamide (7.0 mL) was carried outanalogously to Example 190, Step 2. When the reaction was judged complété, the volatilecomponents were removed in vacuo, and the resulting residue was dissolved in methanol andloaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with1.2:1 dichloromethane: ethyl acetate to afford Intermediate 198(a) (80 mg, 0.169 mmol) as ayellow solid in 46% yield. 25 013017 208 10 15 1H NMR (d6-DMSO): δ 12.64 (s, 1H), 10.47 (s, 1H), 10.16 (s, 1H), 8.06 (d, 1 H, J= 1.51 Hz), 7.66(d, 1 H, J = 1.51 Hz), 7.36 (s, 1H), 6.91 (d, 1H, J- 9.04 Hz), 3.92 (dd, 1H, J = 8.29, 7.91 Hz), 1.78-1.46 (m, 6H), 1.38 (s, 9H), 1.21-0.92 (m, 5H). LCMS: (M-H)‘472.1.

Step 2. Préparation of Title Compound: (R)- 2-Amino-/V-(2-chloro-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-cyclohexyl-acetamide (hydrochloric sait)

Préparation of the title compound from Intermediate 198(a) (75 mg, 0.159 mmol) and 4.0 M HCl indioxane (0.8 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (65 mg, 0.159 mmol) as a yellow powder in 99% yield. 1H NMR (d6-DMSO): δ 12.81 (s, 1H), 10.77 (s, 1H), 10.53 (s, 1H), 8.30 (br s, 3H), 8.03 (d, 1 H, J =1.70 Hz), 7.70 (d, 1 H, J = 1.70 Hz), 7.39 (s, 1H), 3.73 (m, 1H), 1.93-1.55 (m, 6H), 1.27-1.01 (m,5H). LCMS: (M+H+) 374.0; (M-H)' 372.2. HRMS: (M+H+) calcd for C1BH21N5O2CI, 374.1384, found 374.1369.

Example 199: 2-(3,4-Dihvdro-1/-/-isoquinoltn-2-vl)-/\/-f6-oxo-5.6-dihvdro-1H-f1,2ldiazepinor4.5.6- cdlindol-8-vl)-acetamide

-

CS2CO3, DMF

,CO2C2H5

NaOH, MeOH --> 48 °C, 98% 199(a)

„CO2H 199(b)

Title Compoundof Example 2 20

HN—N

HATU, Et3N, DMF, 42%

Step 1. Préparation of (3,4-Dihydro-1H-isoquinoiin-2-yl)-acetic acid ethyl ester 199(a)

To a solution of 1,2,3,4-tetra-hydroisoquinoline (2.664 g, 20 mmol) and ethyl bromoacetate (3.647g, 22 mmol) in /V,/V-dimethylformamide (23 mL), was added Cs2CO3 (7.168 g, 22 mmol) under N2.The mixture was stirred at room température for 4 hours. The solvent was removed underreduced pressure, and the remaining residue was subjected to silica gel chromatography, elutingwith ethyl acetate/hexanes (33:66) to afford Intermediate 199(a) (3.39 g, 15.5 mmol) as yellow oilin 77% yield. 1H-NMR (CDCI3): δ 7.13-7.09 (m, 3H), 6.99 (t, 1H), 4.22 (q, 2H), 3.84 (s, 2H), 3.44 (s, 2H), 2.94(s,4H), 1.29 (t,3H). 25 013017 209 LCMS: (M+H+) 220.3. 10

Step 2. Préparation of (3,4-Dihydro-1H-isoquinolin-2-yl)-acetic acid 199(b)

To a suspension of Intermediate 199(a) (1.643 g, 7.5 mmol) in methanol (20 mL) was added 2.5N NaOH (7.8 mL). The reaction solution was heated at 48 °C and stirred overnight. With cooling,the pH was adjusted to 8 by adding 1M HCl. The volatile components were removed undervacuum, and the resulting mixture was suspended in methanol. After filtration to remove theinsoluble solids, the filtrate was evaporated to give Intermediate 199(b) (1.4 g, 7.3 mmol) as whitefoam in 98% yield. ’H-NMR (de-DMSO): δ 7.13-7.09 (m, 3H), 7.02 (t, 1H), 3.76 (s, 2H), 3.27 (s, 2H), 2.88-2.82 (m,4H). LCMS: (M+H+) 192.2. 15 20

Step 3. Préparation of Title compound: 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-/V-(6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indol-8-yl)-acetamide

Préparation of the title compound from the title compound of Example 2 (185 mg, 0.79 mmol),intermediate 199(b) (150 mg, 0.79 mmol), triethylamine (0.274 mL, 1.98 mmol), O-(7-azabenzotriazol-1-yl)-A/,/V,A/’,/V-tetramethyluronium hexafluorophosphate (330 mg, 0.879 mmol)and /V./V-dimethylformamide (3 mL) was carried out analogously to 11. Following évaporation ofthe volatile components, the resulting residue was triturated with a small amount of N,N-dimethylformamide and water to give the title compound (123.5 mg, 0.331 mmol) as yellow solidin 42% yield. 1H-NMR (de-DMSO): δ 11.73 (s, 1H), 10.22 (s, 1H), 9.97 (s, 1 H), 8.13 (s, 1H), 7.62(s, 1H), 7.55 (s,1H), 7.45 (s, 1H), 7.12-7.04 (m, 4H), 3.72 (s, 2H), 2.88-2.80 (m, 6H). LCMS: (M+H+) 374.4

Example 200: 2-( 1,3-Dihvdro-isoindol-2-yl)-M-(6-oxo-5,6-dihvdro-1 /-/-f1.2ldiazepinor4,5,6-cd1indol- 25

NaOH, MeOH -► 48 °C, 54%

Title Compoundof Example 2 -► HATU, Et3N, DMF, 67% 200(b)

HN—N "-An

013017 210

Step 1. Préparation of (1,3-Dihydro-isoindol-2-yl)-acetic acid ethyl ester 200(a)

Into a solution of isoindoline (1.788 g, 15 mmol) and ethyl bromoacetate (2.756 g, 16.5 mmol) in/V,A/-dimethylformamide (20 mL), was added Cs2CO3 (5.376 g, 16.5 mmol) under N2. The mixturewas stirred at room température for 4 hours. The solvent was removed under reduced pressureand the resulting mixture was subjected to silica gel chromatography, eluting with 33:66 ethylacetate.'hexane to afford Intermediate 200(a) (1.14 g, 5.56 mmol) as a yellow oil in 37% yield.1H-NMR (CDCI3): δ 7.20 (s, 4H), 4.22 (q, 6H), 3.66 (s, 2H), 1.29 (t, 3H). LCMS: (M+H+) 206.3.

Step 2. Préparation of 1,3-Dihydro-isoindol-2-yl)-acetic acid 200(b)

To a suspension of Intermediate 200(a) (1.14 g, 5.56 mmol) in methanol (20 mL) was added 2.5N NaOH (5.78 mL). The reaction solution was heated at 48 °G and stirred overnight. With cooiing,the pH was adjusted to 8 by adding 1M HCl. The volatile components were removed undervacuum and the resulting mixture was suspended in methanol. After filtration to remove theinsoluble solids, the filtrate was evaporated to give Intermediate 200(b) (531 mg, 3 mmol) as palesolids in 54% yield. LCMS: (M+H+) 178.2.

Step 3. Préparation of Title compound: 2-(1,3-Dihydro-Îsoindol-2-yl)-N-(6-oxo-5,6-dihydro-1 H-[1,2]dîazepino[4,5,6-cd]indol-8-yl)-acetamide

Préparation of the title compound from the title compound of Example 2 (118 mg, 0.5 mmol),Intermediate 200(b) (88.5 mg, 0.5 mmol), triethylamine (0.274 mL, 1.98 mmol), O-(7-azabenzotriazol-1-yl)-/V,/V,/V’,/V’-tetramethyluronium hexafluorophosphate (209 mg, 0.55 mmol)and /V./V-dimethylformamide (5 mL) was carried out analogously to Example 11. Followingévaporation of the volatile components, the resulting residue was triturated with a small amount ofW,/V-dimethylformamide and water to give the title compound (121 mg, 0.337 mmol) as a yellowsolid in 67% yield. ’H-NMR (d6-DMSO): δ 11.73 (s, 1H), 10.21 (s, 1H), 10.02 (s, 1H), 8.13 (s, 1H), 7.66(s, 1H), 7.55(s, 1H), 7.46 (s, 1H), 7.22 (d, 4H), 4.07 (s, 4H), 3.56 (s, 2H). LCMS: (M+H+) 360.4

Example 201: (2-Morpholin-4-vl-6-oxo-5,6-dihydro-1A/-i1,2)di3zepinof4,5.6-cdlindol-8-vl)-carbamic acid tert-butvl ester

Triethylamine (0.039 mL, 0.28 mmol), the title compound of Example 187 (46 mg, 0.14 mmol),morpholine (96 mg, 1.1 mmol) and n-butanol (5 mL) were stirred in a flask with a condenser at120 °C overnight. The mixture was allowed to stand at room température for two more days. The 013017 211 volatile components were removed under vacuum and the resulting mixture was subjected tosiiica gel chromatography, eluting with 95:5 dichloromethane:methanol to afford the titlecompound (12.5 mg, 0.032 mmol) as a yellow solid in 23% yield. 'H-NMR (d6-DMSO): δ 9.53 (s, 1H), 8.47 (s, 1H), 7.80 (s, 1H), 7.28 (s, 1 H), 6.06 (s, 2H), 3.74 (s,8H), 1.48 (s, 9H). LCMS: (M+H+) 386.4.

Example 202: i1.2-frans)-2-(3-Bromo-phenvl)-cyclopropanecarboxvlic acid i6-oxo-5.6-dihydro-1H- f1,2idiazepinof4,5.6-cc/lindol-8-vl)-amide

Example 211%

Step 1. Préparation of (1,2-irans)-2-(3-Bromo-phenyl)-cyclopropanecarboxyiic acid ethyiester 202(a)

To a mixture of NaH (186 mg, 4.65 mmol) and trimethylsulfoxonium iodide (1.02 g, 4.65 mmol)was added DMSO (5 mL). After stirring for 30 min, a solution of Érar?s-3-(bromo-phenyl)-acrylicacid ethyi ester (933 mg, 3.57 mmol) in DMSO (2 mL) was added drop-wise. After stirringovemight, the mixture was partitioned between ethyi acetate and water. The aqueous layer wasextracted with ethyi acetate. The combined organic layers were dried over Na2SO4, filtered, andconcentrated. The residue was subjected to siiica gel chromatography, eluting with 10 % ethyiacetate/hexane, to fumish Intermediate 202(a) as a colorless oil (408 mg, 1.52 mmol) in 43%yield.

Step 2. Préparation of Title compound: (1,2-frans)-2-(3-Bromo-phenyl)- cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H-I1,2]diazepino[4,5,6-ccflindol-8-yI)-amide

To a stirred solution of Intermediate 202(a) (505 mg, 2.25 mmol) in MeOH (10 mL) was addedaqueous 10M LiOH (10 mL). The mixture was stirred at 23 °C for 12 hours, acidified with 1 M HCl 013017 212 to pH 1, and extracted with ethyl acetate. The combined organic layers was then washed withbrine and concentrated to give crude (2,3-frans)-3-(3'-bromo-phenyl)-cycloprapanecarboxylic acid(632 mg), which was combined with the title compound of Example 2 (111 mg, 0.49 mmol),triethylamine (0.273 mL, 1.96 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,/tf,/V',/V-tetramethyluronium hexafluorophosphate (278 mg, 0.73 mmol) in A/,W-dimethylformamide (4 mL)in a manner analogous to Example 11. Extractive work-up from ethyl acetate and saturatedaqueous NaHCO3 follow by silica gel chromatography afforded the title compound (100 mg, 0.24mmol) as a yellow solid in 11 % yield. 1H NMR (d6-DMSO): 11.85 (d, 1H, J = 2.26 Hz), 10.50 (s, 1H), 10.35 (s, 1H), 8.23 (s, 1H), 7.69 (s,1H), 7.67 (d, 1H, J = 4.0 Hz), 7.58 (s, 1H), 7.53-7.51 (m, 2H), 7.40-7.33 (m, 2H), 2.53 (m, 1H),2.23 (m, 1 H), 1.62 (m, 1 H), 1.54 (m, 1 H).

Example 203: f1.2-frans)-2-(3-Hydroxv-phenvl)-cvclopropanecarboxvlic acid (6-oxo-5,6-dihvdro- 1 H-Π .21diazepinof4,5.6-cdlindol-8-vl)-amide BBr3, CH2CI2

Intermediate 196(a), ->

Example 196 78 oc, 54%

203(a)

1. LiOH, THF, H2O 2. HATU, Et3N, PMF,Title Compound ofExample 2 5%

HN—N

Step 1. Préparation of 2-(3-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester 203(a)

To a stirred solution of Intermediate 196(a) of Example 196 (1.56 g, 7.12 mmol) in CH2CI2 at -78°C was added 1.0M BBr3 in CH2CI2 (8.56 ml, 8.56 mmol). The mixture was warmed to roomtempérature and stirred for 1 hour. Extractive work-up from ethyl acetate and saturated aqueousNaHCO3 followed by silica gel chromatography afforded Intermediate 203(a) as a pale brown solid(795 mg, 3.86 mmol) in 54% yield.

Step 2. Préparation of Title compound: (1,2-frans)-2-(3-Hydroxy-phenyI)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-y[)-amide

To a solution of Intermediate 203(a) (271 mg, 1.32 mmol) in tetrahydrofuran (2 mL) was addedaqueous 1M LiOH (6 mL, 6 mmol). The mixture was stirred overnight. After acidifying to pH 2, themixture was extracted with ethyl acetate. Concentration of the organic layer gave crude 3-(3- 013017 213 hydroxy-phenyl)-cycloprapanecarboxylic acid (235 mg), where a portion (155 mg, 0.57 mmol)was combined with the title compound of Example 2 (137 mg, 0.58 mmol), triethylamine (0.24 mL,1.72 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/\/-tetramethyluronium hexafluorophosphate(331 mg, 0.87 mmol) in W,W-dimethylformamide (3 mL) in a manner analogous to Example 11. 5 Extractive work-up from ethyl acetate and saturated aqueous NaHCC>3 followed by silica gelchromatography afforded the title compound (10 mg, 0.028 mmol) as a tan solid in 5% yield. 1H NMR (d6-DMSO): δ 10.35 (s, 1H), 10.27 (s, 1H), 9.35 (s, 1H), 8.12 (s, 1 H), 7.67 (dd, 1 H, J =3.20, 1.51 Hz), 7.55 (s, 1H), 7.48(s, 1H), 7.15 (t, J= 8.0 Hz, 1H), 6.77-6.74 (m, 3H), 2.32 (m, 1H),2.09 (m, 1H), 1.45 (m, 1H), 1.38 (m, 1H). 10 LCMS: (M-H+) 359.1

Example_204_2-(3.4-Dihvdroisoauinoiin-2(1H)-vl)-/V-(6-oxo-2-phenvl-5.6-dihvdro-1/V- f1.2ldiazepino[4.5,6-cdlindol-8-vl)acetamide

HN-N

In a manner analogous to that of Example 11, to a stirred solution of 8-amino-1,5-dihydro-6H- 15 [1,2]diazepino[4,5,6-cd] indol-6-one in anhydrous Λ/,/V-dimethylformamide (6 mL) was added 3,4- dihydroisoquinolin-2(1H)-ylacetic acid (62 mg, 0.33 mmol) followed by triethylamine (0.14 mL,0.98 mmol) and 0-(7-azabenzotriazol-1-yl)-/V,/V,A/’,/V'-tetramethyluronium hexafluorophosphate(372 mg, 0.98 mmol). The reaction was stirred at room température for 17 hours. Afterconcentrating, water was added and the precipitated solid was collected by filtration. After 20 préparative HPLC, the title compound (50 mg) was obtained as a yellow powder in 34% yield. 1H NMR (methanol-cL,) d: 3.25 (2H, m), 3.72 (2H, bs), 4.27 (2H, s), 4.58 (2H, s), 7.22 (1H, d, J =7.58 Hz), 7.32 (3H, m), 7.52 (4H, m), 7.63 (3H, m), 8.13 (1H, d, J = 1.52 Hz). LCMS: (M+H+) 450.1.

Example 205: (1.2-frans)-2-Pyridin-3-vl-cvclopropanecarboxylic acid (2-chloro-6-oxo-5,6-dihvdro- 25 1/-/-[1,21diazepinof4,5.6-cd1indol-8-vh-amide (hvdrochloric sait)

HN-N

The title compound of Example 191 (20 mg, 0.053 mmol) was converted to an HCl sait inanhydrous CH2CI2 (2mL) with 4.0 M HCl in dioxane (0.026 mL). The mixture was stirred at roomtempérature for 1 hour. The solid was collected by filtration and washed with CH2CI2 and diethyl 30 ether. After drying, the title compound (20.4 mg, 0.049 mmol) was obtained as a yellow powder in93% yield. 013017 214 1H NMR (de-DMSO): δ 12.70 (s, 1H), 10.59 (s, 1H), 10.46 (s, 1H), 8.85 (s, 1H), 8.72 (d, 1H, J =5.84 Hz), 8.25 (d, 1H, J = 8.29 Hz), 8.07 (d, 1H, J = 1.70 Hz), 7.91 (dd, 1H, J = 5.27, 5.27 Hz),7.63 (d, 1 H, J = 1.70 Hz), 7.35 (ε, 1H), 2.75-2.59 (m, 1H), 2.33-2.21 (m, 1H), 1.67-1.56 (m, 2H).Example 206: (1R.2R)- 2-Phenyl-cyclopropanecarboxyiic acid (2-bromo-6-oxo-5.6-dihvdro-1/7- ri.21diazepinof4,5,6-ccf|indol-8-yl)-amide

Intermediate 147(d),Example 147

EDCI, E^N, 4-DMAPDMF, 33%

HN—N

Step 1. Préparation of 8-Amino-2-bromo-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one(hydrochloric sait) 206(a)

Préparation of intermediate 206(a) from Intermediate 147(d) of Example 147 (2 g, 5.29 mmol) and 10 4.0 M HCl in dioxane (26.4 mL) was carried out analogously to Example 91. Isolation, aiso in an analogous manner, afforded Intermediate 206(a) (1.59 g, 5.04 mmol) as a yellow powder in 96%yield. 1H NMR (d6-DMSO): δ 13.13 (s, 1H), 10.67 (s, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H). LCMS: (M+H+) 279.0, 281.1, (M+Na+) 401,0,403.0; (M-H)’ 277.0, 279.0. 15 Step 2. Préparation of Title Compound: (1R,2R)- 2-Phenyl-cyciopropanecarboxylic acid (2-bromo-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indol-8-y!)-amidePréparation of the title compound from Intermediate 206(a) (120 mg, 0.380 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (74.0 mg, 0.457 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (88 mg, 0.461 mmol), and 4-dimethylaminopyridine (56 mg, 0.459 20 mmol) in W,N-dimethylformamide (15.0 mL) was carried out analogously to Example 190, step 2.When the reaction was judged complété, the volatile components were removed in vacuo, and theresulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was thenloaded onto a silica gel column and eluted with 1.2:1 dichloromethane: ethyl acetate to afford thetitle compound (52.4 mg, 0.124 mmol) as a yellow solid in 33% yield. 25 1H NMR (ds-DMSO): δ 12.59 (s, 1H), 10.45 (s, 1H), 10.44 (s, 1H), 8.08 (d, 1H, J= 1.51 Hz), 7.60(d, 1H, J= 1.70 Hz), 7.33-7.24 (m, 3H), 7.24-7.13 (m, 3H), 2.42-2.32 (m, 1H), 2.11-2.00 (m, 1H),1.54-1.42 (m, 1H), 1.42-1.30 (m, 1H). 013017 215 LCMS: (M+H+) 423.0,425.0, (M+Na+) 445.0,447.0; (M-H)' 421.0, 423.0. HRMS: (M+H+) calcd for C2oH16N402Br( 423.0457, found 423.0471.

Example 207: A/-Methy[-A/-(2-methvlprop-2-envl)-/\/'-i6-oxo-5.6-ciihvdro-1 H-l 1.21diazepino(4.5,6- canindol-8-vhurea

HN—N

Using a similar route as outlined in Example 192, the title compound of Example 2 (25 mg, 0.11mmol) and ty/V-disuccinimidyl carbonate (27 mg, 0.11 mmol) were stirred together in N,N-dimethylformamide (1 mL) while /V,/V-diisopropylethylamine (0.024 mL, 0.21 mmol) was added.After stirring three minutes W-2-dimethylprop-2-en-1-amine (0.046 mL, 0.21 mmol) was addedgiving the crude product. Cation-exchange polystyrène scavenging resin (ArgonautTechnologies™, MP-TsOH) was added directly to the mixture. After stirring 2 hours the resin wasremoved by filtration and washed twice with Λ/,/V-dimethylformamide (1 mL). The combined N,N-dimethylformamide solutions were then treated with anion-exchange polystyrène scavenging resin(Argonaut Technologies™, MP-carbonate) and stirred for 2 hours. Again the resin was removedby filtration and washed twicé with W,A/-dimethylformamide (1 mL). The combined N,N-dimethylformamide solutions were then reduced under vacuum and subjected to préparativeRPHPLC (Peeke Scientific Hl-Q, C18 reverse-phase, .5 uM, 100A, 150x20 mm column) elutingwith 0.1% acetic acid in CH3CN and 0.1% acetic acid in H2O at a fiowrate of 20 mL/min using agradient of 30-70% 0.1% acetic acid in CH3CN over 30 min. Fractions judged pure were pooled,and the volatile components removed in vacuo. After a final trituation with ethyl acetate, the titlecompound (6 mg, 0.019 mmol) was obtained as brown powder in 18% yield. 1H NMR (CDCI3/methanol-d4): δ 7.90 (s, 1H), 7.42 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 4.98 (s, 1H),4.90 (s, 1 H), 3.95 (s, 2H), 3.03 (s, 3H), 1.77 (s, 3H). LCMS: (M+H+) 312.2, (M+Na+) 334.1.

Example 208:_A/-Methvl-/V-(6-oxo-5.6-dihvdro-1H-f1.21diazepinof4.5.6-ccf|indol-8-vl)-/V- (phenylmethvl)urea

HN—N

Préparation of example 208 from the title compound of Example 2 (48 mg, 0.20 mmol), Λ/,ΛΓ- disuccinimidyl carbonate (52 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol) and W-methyl- 1-phenylmethanamine (0.052 mL, 0.40 mmol) in Λ/,/V-dirnethylformamide (0.5 mL) was carried out 013017 216 analogously to Example 192. Purification, also in an analogous manner, afforded the titlecompound (8 mg, 0.023 mmol) was obtained as brown powder in 12% yield. 1H NMR (CDCIg/methanoK): δ 7.88 (s, 1H), 7.46-7.23 (m, 8H), 4.64 (s, 2H, obscured), 3.03 (s,3H). LCMS: (M+H+) 348.4, (M+Na+) 370.4.

Example 209: (1.2-frans)-2-f2'-Methoxv-phenvl)-cyclopropanecarboxvlic acid (6-oxo-5.6-dihvdro- 1 W1,21diazepinof4,5.6-cdlindol-8-vl)-amide

Wle3SO+r, NaH ->. DMSO, 43%

:O2Et

1. LiOH, THF, H2O ->. 2. HATU.Et3N.DWlF,

Title Compound ofExample 2 209(a)

10 15 10%

Step 1: Préparation of (1,2-fra/is)-2-(2’-Methoxy-phenyl)-cyclopropanecarboxylic acid ethylester 209(a)

Préparation of intermediate 209(a) from NaH (1.04 g, 26 mmol) and trimethylsulfoxonium iodide(5.72 g, 26 mmol), 2-(methoxy-phenyl)-acrylic acid ethyl ester (4.12 g, 20 mmol) indimethylsulfoxide (30 mL) was carried oui analogously to step 2 of Example 113. Intermediate209(a) (1.89 g, 8.6 mmol) was obtained in 43% yield.

Step 2: Préparation of Title compound: (1,2-irans)-2-(2’-Methoxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-ditiydro-1 H-[1,2]diazepino[4,5,6-coQindol-8-yl)- amide

Préparation of the title compound was carried out analogously to step 3 of Example 172 exceptthat Intermediate 209(a) was used instead of Intermediate 172(b). The title compound wasobtained in 10% yield. 1H NMR (d6-DMSO): δ 11.74 (d, 1H, J = 2.26 Hz), 10.35 (s, 1H), 10.24 (s, 1H), 8.14 (s, 1H), 7.57(dd, 1H, J=3.20, 1.51 Hz), 7.46 (ε, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.77-6.74 (m, 3H), 3.80 (s, 3H),2.36 (m, 1H), 2.02 (m, 1H), 1.44 (m, 1H), 1.34 (m, 1H). LCMS: (M-H+) 373.1. 20 013017

Example 210: /V-cvclohexyl-/V-methvl-fV’-(6-oxo-5,6-dihvdro-1 H-F1,21diazepinoi4,5,6-cdlindol-8- vOurea

HN—N 10 15 20 217

Préparation of example 210 from the title compound of Example 2 (25 mg, 0.11 mmol), Ν,Ν'-disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diïsopropylethylamine (0.024 mL, 0.21 mmol)and W-cyclohexyl-/V-methylamine (0.028 mL, 0.021 mmol) in Λ/,/V-dimethylformamide (1.0 mL)was carried out analogously to Example 207. Purification, also in an analogous manner, affordedthe title compound (7 mg, 0.021 mmol) as yellow powder in 19% yield. 1H NMR (CDCh/methanol-dJ: δ 7.90 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 4.09 (m, 1H),2.92 (s, 3H), 1.91-1.80 (m, 2H), 1.79-1.65 (m, 3H), 1.56-1.37 (m, 4H), 1.14 (m, 1H). LCMS: (M+H+) 340.2, (M+Na+) 362.1.

Example 211 : A/-Cvciohexyl-/V-ethvl-AM6-oxo-5,6-dihvdro-1 H-11.21diazepinof4,5.6-cdlindol-8- yQurea

HN-N

Préparation of example 211 from the title compound of Example 2 (25 mg, 0.11 mmol), N,I\T-disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diisopropylethylamine (0.024 mL, 0.21 mmol)and /V-cyclohexyl-/V-methylamine (0.032 mL, 0.021 mmol) in Λ/,/V-dimethylformamide (1.0 mL)was carried out analogously to Example 207. Purification, also in an analogous manner, affordedthe title compound (7 mg, 0.020 mmol) as yellow powder in 20% yield. 1H NMR (CDCI3/methanol-d4): δ 7.94 (s, 1H), 7.40 (s, 1H, obscured), 7.30 (s, 1H, partiallyobscured), 7.26 (s, 1H), 4.05 (m, 1H, partially obscured), 3.36 (m, 2H, partially obscured), 1.90-1.74 (m, 4H), 1.71 (m, 1H), 1.58-1.33 (m, 4H), 1.26 (t, 3H, J = 7.16 Hz), 1.14 (mf 1H). LCMS: (M+H+) 354.2, (M+Na+) 376.1.

Example 212: A/,/V-Diethyl-/V-(6-oxo-5,6-dihydro-1H-f1.21diazepinof4.5.6-cdlindol-8-vl)urea

25

Préparation of example 212 from the title compound of Example 2 (25 mg, 0.11 mmol), Λ/,ΛΓ- disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diisopropylethylamine (0.024 mL, 0.21 mmol) 013017 218 and /V,/V-diethylamine (0.022 mL, 0.021 mmol) in Λ/,ΛΖ-dimethylformamide (1.0 mL) was carriedout analogously to Example 207. Purification, also in an analogous manner, afforded the titlecompound (5 mg, 0.016 mmol) as yellow powder in 15% yield. 1H NMR (CDCl3/methanol-d4): δ 7.91 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 3,42 (q, 4H,5 J = 7.16 Hz), 1.24 (t, 6H, J = 7.16 Hz). LCMS: (M+H+) 300.2, (M+Na+) 322.1.

Example 213: A/-(6-Oxo-5,6-dihvdro-1 H-11.2)diazepino[4.5,6-cdlindol-8-vl)piperidine-1- carboxamide

10 Préparation of example 213 from the title compound of Example 2 (25 mg, 0.11 mmol), N.N1-disuccinimidyl carbonate (27 mg, 0.11 mmol), W,W-diisopropylethylamine (0.024 mL, 0.21 mmol)and piperidine (0.021 mL, 0.021 mmol) in /V,A/-dimethylformamide (1.0 mL) was carried outanalogously to Example 207. Purification, also in an analogous manner, afforded the titlecompound (7 mg, 0.022 mmol) as yellow powder in 20% yield. 15 ’H NMR (CDCl3/methanol-d4): δ 7.77 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H, partialiy obscured),. 7.32 (s,1 H), 3.57-3.47 (m, 4H), 1.76-1.56 (m, 6H). LCMS: (M+H+) 312.1, (M+Na*) 334.1.

Préparation of example 214 from the title compound of Example 2 (25 mg, 0.11 mmol), Λ/,ΛΓ-disuccinimidyl carbonate (27 mg, 0.11 mmol), W,/M-diisopropylethylamine (0.024 mL, 0.21 mmol)and 4-(phenylmethyl)piperidine (0.037 mL, 0.021 mmol) in Λ/,/V-dimethylformamide (1.0 mL) wascarried out analogously to Example 207. Purification, also in an analogous manner, afforded the • 25 title compound (7 mg, 0.017 mmol) as yellow powder in 16% yield. 1H NMR (CDCl3/methanol-d4): δ 7.88 (s, 1H), 7.44-7.39 (m, 2H, partialiy obscured), 7.34-7.12 (m, 6H), 4.16 (d, 2H, J = 13.75 Hz), 2.91-2.78 (m, 2H), 2.62-2.57 (m, 2H), 1.80-1.69 (m, 3H), 1.36- 1.14 (m, 2H). LCMS: (M+H+) 402.2, (M+Na+) 424.1. 013017

Example 215:_A/-Ethvl-A/’-(6-oxo-5,6-dihvdro-1/-/-(1,21diazepinof4,5,6-cdlindol-8-vl)-A/- (phenvlmethyl)urea

HN-N 219

Préparation of example 215 from the title compound of Example 2 (25 mg, 0.11 mmol), A/,/V-5 disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diisopropylethylamine (0.024 mL, 0.21 mmol)and /V-(phenylmethyl)ethanamine (0.032 mL, 0.021 mmol) in /V,/V-dimethylformamide'(1.0 mL)was carried out analogousiy to Example 207. Purification, also in an analogous manner, afforded the title compound (7 mg, 0.019 mmol) as yellow powder in 18% yield. 1H NMR (CDCl3/methanol-d4). δ 7.94 (s, 1H), 7.46-7.21 (m, 8H, partially obscured), 4.63 (s, 2H),10 3.51-3.34 (m, 2H, partially obscured), 1.28-1.19 (m, 3H). LCMS: (M+H+) 362.1, (M+Na*) 384.0.

Example 216: /V-Butvl-A/-methvl-/V-(6-oxo-5.6-dihvdro-1 H-H ,21diazepinof4.5.6-crtlindol-8-vl)urea

Préparation of example 216 from the title compound of Example 2 (25 mg, 0.11 mmol), Ν,Ν-15 disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diisopropylethylamine (0.024 mL, 0.21 mmol)and /V-ethyl-W-propylamine (0.025 mL, 0.021 mmol) in /V,/V-dimethylformamide (1.0 mL) wascarried out analogousiy to Example 207. Purification, also in an analogous manner, afforded the title compound (4 mg, 0.013 mmol) as yellow powder in 12% yield. 1H NMR (CDCl3/methanol-d4): δ 7.92 (s, 1H), 7.41 (s, 1H, partially obscured), 7.29 (s, 1H), 7.26 (s,20 1H), 3.04 (s, 3H), 1.66-1.55 (m, 2H), 1.45-1.21 (m, 4H), 0.97 (t, 3H, J = 7.35 Hz). LCMS: (M+H+) 314.1, (M+Na+) 336.2.

Example 217: /V-Methyl-/\/'-(6-oxo-5,6-dihydro-1/V-ri,21diazepinof4.5,6-CGflindol-8-vD-/V-propvlurea

Préparation of example 217 from the title compound of Example 2 (25 mg, 0.11 mmol), Ν,Ν- 25 disuccinimidyl carbonate (27 mg, 0.11 mmol), Λ/,/V-diisopropylethylamine (0.024 mL, 0.21 mmol) and Λί-ethyl-N-propylamine (0.022 mL, 0.021 mmol) in W,W-dimethylformamide (1.0 mL) was 013017 220 carried out analogously to Example 207. Purification, also in an analogous manner, afforded thetitle compound (4 mg, 0.013 mmol) as yellow powder in 12% yield. 1H NMR (CDCIa/methanol-d^: δ 7.87 (s, 1 H), 7.43 (s, 1H), 7.36 (s, 1 H), 7.29 (s, 1H), 3.05 (s, 3H),1.72-1.58 (m, 2H), 1.37-1.21 (m, 2H), 0.96 (t, 3H, J = 7:25 Hz) 5 LCMS: (M+H+) 300.2, (M+Na+) 322.1.

Example 218: f1,2-frans)-2-r3-(2-Dimethvlamino-ethoxv)-phenvH-cvclopropanecarboxvlic acid (6- oxo-5.6-dihvdro-1 H41.21diazepino[4,5.6-ctflindol-8-yl)-amide

Intermediate 203(a),Example 203

•Et -► PPh3, DIAD, CH2CI260% 218(a)

Title Compound ofExample 2 13% 10

Step 1. Préparation of (1,2-trans)-2-[3-(2-Dimethylamino-ethoxy)-phenyl]-cyclopropanecarboxylic acid 218(a)

To a stirred solution of Intermediate 203(a) of Example 203 (125 mg, 0.607 mmol), 2-dimethylethanol (81 mg, 0.91 mmol) and triphenylphosphine (239 mg, 0.91 mmol) in CH2CI2 was 15 added diisopropyl azodicarboxylate (184 mg, 0.91 mmol). The mixture was stirred at roomtempérature for 4 hours, concentrated, and subjected to silica el chromatography, eluting with 20-30% ethyl acetate/hexane, to furnish Intermediate 218(a) as a colorless oil (101 mg, 0.36 mmol)in 60% yield.

Step 2. Préparation of Title compound: (1,2-frans)-2-[3-(2-Dimethylamino-ethoxy}-phenyl]- 20 cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yI)-amide

Préparation of the title compound was carried out analogously to step 3 of Example 172 exceptthat Intermediate 218(a) was used instead of Intermediate 172(b). The title compound wasobtained in a 13% yield. 25 1H NMR (d6-DMSO): δ 11.56 (d, 1 H, J = 2.26 Hz), 10.20 (s, 1H), 10.06 (s, 1H), 7.95 (d, 1H, J =1.88 Hz), 7.38 (dd, 1H, J = 3.20, 1.51 Hz), 7.29 (s, 1H), 7.04 (t, 1 H, J =8.0 Hz), 6.62-6.58 (m, 3H),6.36 (s, 1H), 3.96-3.94 (m, 2H), 3.12-3.10 (m, 2H), 2.29 (m, 1H), 1.91 (m, 1H), 1.31 (m, 1H), 1.20(m, 1H). 013017 221 LCMS: (M+H+) 432.2.

Example 219: (R)- 2-Amino-2-cvclohexvl-/V-f6-oxo-2-(1,2.3,6-tetrahvdro-pyridin-4-vl)-5.6-dihvdro- 1W1,2)diazepinof4.5.6-cdlindol-8-vll-acetamide: dihvdrochloride

OyL

Intermediate 220(a), _NHBoc

Example 220 EDC|, Ew 4_DMAp DMF, 88%

H—Cl

Step 1. Préparation of (R)- 4-[8-{2-iert-Butoxycarbonylamino-2-cyclohexyl-acetylamino)-6-oxo-5s6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-2-yI]-3,6-dihydro-2H-pyridine-1-carboxylicacid ierf-butyl ester 219(a) 10 Préparation of intermediate 219(a) from Intermediate 220(a) of Example 220 (100 mg, 0.262mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (74.3 mg, 0.289 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (55 mg, 0.288 mmol), and 4-dimethylaminopyridine (35.2 mg, 0.288 mmol) in N,/V-dimethytformamide (6.0 mL) was carried outanalogousiy to Example 190, step 2. When the reaction was judged complété, the volatile 15 components were removed in vacuo, and the resuiting residue was dissolved in methanol andloaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with1:1 dichloromethane: ethyl acetate to afford Intermediate 219(a) (143 mg, 0.231 mmol) as ayellow solid in 88% yield. 1H NMR (d6-DMSO): δ 11.70 (s, 1H), 10.27 (s, 1 H), 10.09 (s, 1 H), 8.06 (d, 1H, J= 1.51 Hz), 7.59 20 (s, 1H), 7.51 (s, 1H), 6.88 (d, 1H, J = 8.10 Hz), 6.17 (s, 1H), 4.06 (br s, 2H), 3.92 (dd, 1H, J = 8.48, 7.72 Hz), 3.55 (t, 2H, J = 5.65, 5.27 Hz), 3.32 (m, 2H, obscured), 1.76-1.46 (m, 6H), 1.43 (s,9H), 1.37 (s, 9H), 1.19-0.94 (m,5H). LCMS: (M-H)'619.2. 013017 222

Step 2. Préparation of Title Compound: (R)- 2-Amino-2-cyclohexyl-A/-[6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide;dihydrochloride

Préparation of the title compound from Intermediate 219(a) (143 mg, 0.231 mmol) and 4.0 M HCl5 in dioxane (2.3 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, afforded the title compound (100 mg, 0.203 mmol) as a red powder in 88% yield. 1H NMR (de-DMSO): δ 12.18 (s, 1H), 10.87 (s, 1H), 10.39 (s, 1H), 9.32 (br s, 2H), 8.35 (br s, 3H),8.07 (d, 1H, J = 1.51 Hz), 7.70 (d, 1H, J = 1.51 Hz), 7.55 (d, 1H, J = 1.51 Hz), 6.19 (s, 1H), 3.87-3.74 (m, 3H), 3.41-3.26 (m, 2H), 2.81-2.69 (m, 2H), 1.90-1.55 (m, 6H), 1.28-0.97 (m, 5H). 10 LCMS: (M+H+) 421.1, (M+Na+) 443.1; (M-H)" 419.1. HRMS: (M+H+) calcd for C23H29N6O2, 421.2352, found 421.2338.

Example 220: (1R.2R)- 2-Phenvl-cvclopropanecarboxvlic acid f6-oxo-2-(1.2,3.6-tetrahvdro-pyridin- 4-vl)-5,6-dihvdro-1 H-F1,21diazepinof4.5.6-ccflindol-8-vn-amide (hvdrochloric sait)

Intermediate 206(a),Example 206

Pd(dppf)CI2, 2 M Na2CO3DMF, 80 °C, 82%

DMF, 94%

4N HCl (Dioxane) ->. CH2CI2, 94%

15 Step 1. Préparation of4-(8-Amino-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indoI-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid terf-butyl ester 220(a)

In a manner analogous to that of Example 184, 2.0 M aqueous Na2CO3 (0.66 mL) was added to amixture of Intermediate 206(a) of Example 206 (1 g, 3.17 mmol), 4-(4,4,5,5-tetramethyl- [1,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid iert-butyl ester (1.18 g, 3.82 20 mmol) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.13 g, 0.159 mmol) inanhydrous /V,/V-dimethylformamide (50 ml), and the reaction was heated at 80 °C for 16 hours. 013017 223

When the reaction was judged complété, the volatile components were removed in vacuo. Ethylacetate (50 mL), methanol (5 mL) and H2O (500 mL) were added, and the aqueous layer wasextracted with ethyl acetate (3X20 mL). The combined ethyl acetate extracts were washed withH2O (2X50 mL) and brine (50 mL) and allowed to dry over Na2SO4. Following filtration, the volatile 5 components were removed in vacuo and CH2CI2 was added to the residue. The resulting solidwas collected by filtration and washed with CH2CI2 and diethyl ether to afford Intermediate 220(a)(1 g, 2.62 mmol) as a red solid in 82% yield. 1H NMR (d6-DMSO): δ 11.15 (s, 1H), 10.04 (s, 1H), 7.42 (s, 1H), 6.92 (d, 1H, J= 1.88 Hz), 6.56. (d, 1H, J= 1.88 Hz), 6.05 (brs, 1H), 5.17 (s, 2H), 4.03 (s, 2H), 3.53 (t, 2H, J = 5.65, 5.27 Hz), 3.36 10 (m, 2H, partially obscured), 1.42 (s, 9H). LCMS: (M+H+) 382.1, (M+Na+) 404.3; (M-H)‘ 380.1.

Step 2. Préparation of (1R,2R)- 4-{6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1A/-[1,2]diazepîno[4,5,6-cc(lindol-2-yl}-3,6-dihydro-2/7-pyridine-1-carboxylic acidferf-butyi ester 220(b) 15 Préparation of intermediate 220(b) from Intermediate 220(a) (100 mg, 0.262 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (47.0 mg, 0.290 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide, hydrochloride (55 mg, 0.288 mmol), and 4-dimethylaminopyridine (35.2 mg, 0.288mmol) in /V,/V-dimethylformamide (6.0 mL) was carried out analogously to Example 190, step 2.When the reaction was judged complété, the volatile components were removed in vacuo, and the 20 resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was thenloaded onto a silica gel column and eluted with 1:1 dichloromethane: ethyl acetate to affordIntermediate 220(b) (130 mg, 0.248 mmol) as a yellow solid in 94% yield. 1H NMR (d6-DMSO): δ 11.71 (s, 1H), 10.39 (s, 1H), 10.26 (s, 1H), 8.07 (d, 1H, J= 1.70 Hz), 7.57(d, 1 H, J = 1.70 Hz), 7.50 (s, 1H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 3H), 6.16 (s, 1H), 4.08-4.04 25 (m, 2H), 3.55 (t, 2H, J = 5.65, 5.27 Hz), 3.35 (m, 2H, obscured), 2.41-2.33 (m, 1H), 2.11-2.02 (m, 1 H), 1.53-1.46 (m, 1 H), 1.43 (s, 9H), 1.40-1.30 (m, 1 H). LCMS: (M-H)’ 524.1.

Step 3. Préparation of Title Compound: (1R.2R)- 2-Phenyl-cyciopropanecarboxyiic acid [6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]- 30 amide (hydrochloric sait)

Préparation of the title compound from Intermediate 220(b) (130 mg, 0.248 mmol) and 4.0 M HClin dioxane (1.24 mL) was carried out analogously to Exampie 91. Isolation, also in an anaiogousmanner, afforded the title compound (107 mg, 0.232 mmol) as a red powder in 94% yield. ’H NMR (d6-DMSO): δ 11.97 (s, 1H), 10.47 (s, 1H), 10.33 (s, 1H), 9.31-9.10 (br s, 2H), 8.11 (d, 35 1H, J = 1.70 Hz), 7.61 (d, 2H, J = 1.70 Hz), 7.53 (s, 1H), 7.34-7.24 (m, 2H), 7.24-7.12 (m, 3H), 013017 224 6.17 (s, 1H), 3.87-3.72 (m, 2H), 3.40-3.25 (m, 2H), 2.80-2.66 (m, 2H), 2.42-2.31 (m, 1H), 2.15-2.04 (m, 1H), 1.55-1.42 (m, 1 H), 1.42-1.29 (m, 1H). LCMS: (M+H+) 426.0, (M+Na+) 448.1 ; (M-H)' 424.1. HRMS: (M+H+) calcd for C25H24N5O2) 426.1930, found 426.1924. 5 Example 221: (1,2-fr~a/?s)-2-Pvridin-3-vl-cvclopropanecarboxvlic acid f6-oxo-2-(1,2,3.6-tetrahvdro-

Pvridin-4-yl)-5,6-dihvdro-1 H-Π .21diazepinof4,5,6-cc/lindol-8-vll-amide; dihvdrochloride

Intermediate 220(a),Example 220 4N HCl (Dioxane) ->. CH2CI2, 99%

Step 1. Préparation of (1,2-frans)-4-{6-Oxo-8-[(2-pyridin-3-yl-cyclopropanecarbonyl)-amino]- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc(]indol-2-yl}-3,6-dihydro-2H-pyridine-1 -carboxyiic acid 10 iert-butyl ester 221 (a)

Préparation of intermediate 221(a) from Intermediate 220(a) of Example 220 (100 mg, 0.262mmol), crude 2-pyridin-3-yl-cyclopropanecarboxylic acid (estimated purity c.a. 75%) (67.3 mg, c.a.0.289 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (55 mg, 0.288 mmol),and 4-dimethylaminopyridine (35.2 mg, 0.288 mmol) in A/./V-dimethylformamide (10.0 mL) was 15 càrried out analogously to Example 190, step 2. When the reaction was judged complété, thevolatile components were removed in vacuo, and the resulting residue was dissolved in methanoland loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and elutedwith 20:1 dichloromethane: methanol to afford Intermediate 221(a) (107.6 mg, 0.204 mmol) as ayellow solid in 78% yield. 20 1H NMR (d6-DMSO): δ 11.72 (s, 1H), 10.42 (s, 1H), 10.26 (s, 1H), 8.50 (s, 1H), 8.40 (d, 1H, J =4.71 Hz), 8.07 (s, 1H), 7.57 (s, 1H), 7.55 (d, 1 H, J = 7.91 Hz), 7.50 (s, 1H), 7.32 (dd, 1H, J = 4.71,3.77 Hz), 6.16 (s, 1H), 4.05 (br s, 2H), 3.55 (t, 2H, J = 4.52, 4.71 Hz), 3.35 (m, 2H, obscured),2.46-2.37 (m, 1H), 2.16-2.06 (m, 1H), 1.57-1.48 (m, 1H), 1.43 (s, 9H), 1.48-1.38(m, 1H). LCMS: (M+H+) 527.2; (M-H)' 525.0. 013017 225 10

Step 2. Préparation of Title Compound: (1,2-frans)-2-Pyridin-3-yl-cyclopropanecarboxylicacid [6-oxo-2-(1,2,3,6-tetrabydro-pyridin-4-yl)-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cc(]indol-8-yl]-amide; dihydrochioride

Préparation of the title compound from Intermediate 221(a) (100 mg, 0.190 mmol) and 4.0 M HClin dioxane (0.95 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (95 mg, 0.190 mmol) as a red powder in 99% yield. 1H NMR (d6-DMSO): δ 12.05 (s, 1H), 10.66 (s, 1H), 10.34 (s, 1H), 9.29 (br s, 2H), 8.89 (d, 1H, J =1.51 Hz), 8.74 (d, 1H, 0 = 5.27 Hz), 8.32 (d, 1H, J = 8.48 Hz), 8.10 (d, 1H, J= 1.51 Hz), 7.94 (dd,1H, J = 6.03, 5.65 Hz), 7.65 (d, 1H, J = 1.51 Hz), 7.53 (s, 1H), 6.17 (s, 1H), 3.85-3.74 (m, 2H),3.38-3.25 (m, 2H), 2.80-2.70 (m, 2H), 2.70-2.59 (m, 1H), 2.40-2.29 (m, 1H), 1.69-1.55 (m, 2H).LCMS: (M+H+) 427.1, (M+Na+) 449.1 ; (M-H)‘ 425.0. HRMS: (M+H+) calcd for C^H^NeC;»,427.1882, found 427.1895.

Example 222: (1R,2R)-2-Phenvl-cvclopropanecarboxvlic acid (6-oxo-2-piperidin-4-vl-5.6-dihvdro- 1 W1.2ldiazepinof4.5.6-cdlindol-8-vl)-amide (hvdrochloric sait)

Intermediate 220(a), pd,c· H2. MeOH

Example 220 - DMF, 29%

15

HATU, Et3N, DMF

HN-N

NH.HCI 4N HCl (Dioxane) CH2CI2, 90%

Step 1. Préparation of 4-(8-Amino-6-oxo-5,e-dihvdro-1H-f1.2ldiazepinof4.5,6-ccnindol-2-vl)- piperidine-1-carboxvlic acid ferf-butvi ester 222(a)

In a manner analogous to that of Example 183, palladium (10% on activated carbon) (0.186 g)was added to a solution of Intermediate 220(a) of Example 220 (0.61 g, 1.60 mmol) in 9:1methanol:/V,/V-dirnethformamide (50 mL). The reaction mixture was purged with H2 and stirred atroom température under H2 (1 atm.) for 6.5 hours. The mixture was fiitered, and the filtrateevaporated. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. 20 013017 226

The plug was then loaded onto a silica gel column and eluted with 50:3dichioromethane.methanol to give Intermediate 222(a) (0.18 g, 0.470 mmol) as a yellow solid in29% yield. 1H NMR (d6-DMSO): δ 11.03 (s, 1H), 9.88 (s, 1 H), 7.43 (s, 1H), 6.86 (s, 1H), 6.54 (s, 1H), 5.04 (brs, 2H), 4.16-3.99 (m, 3H), 2.95-2.67 (m, 2H), 1.73-1.54 (m, 4H), 1.42 (s, 9K). LCMS: (M+H+) 384.1, (M+Na+) 406.2; (M-H)' 382.1.

Step 2. Préparation of (1R,2R)- 4-{6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-2-yl}-piperidine-1-carboxylic acid terf-butyl ester222(b)

Préparation of intermediate 222(b) from Intermediate 222(a) (60 mg, 0.157 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (27.9 mg, 0.172 mmol), triethylamine (0.086 mL, 0.617mmol), and O-(7-azabenzotriazol-1-yl)-W,W,W',W’-tetramethyluronium hexafluorophosphate (71.5mg, 0.188 mmol) in Λ/,/V-dimethylformamide (5.0 mL) was carried out analogously to Example 11.The volatile components were removed in vacuo, and the resulting residue was dissolved inmethanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column andeluted with 1:1 dichloromethane: ethyl acetate to afford Intermediate 222(b) (104 mg) as a yellowsolid contaminated with Λ/,/V-dimethylformamide which was carried on directly to the next step. 1H NMR (de-DMSO): δ 11.57 (s, 1H), 10.32 (s, 1H), 10.12 (s, 1H), 7.98 (s, 1H), 7.55 (d, 1H, J =1.32 Hz), 7.54 (s, 1H), 7.33-7.25 (m, 2H), 7.22-7.15 (m, 3H), 4.19-4.00 (m, 3H), 2.92-2.77 (m,2H), 2.41-2.30 (m, 1H), 2.12-2.00 (m, 1H), 1.80-1.56 (m, 4H), 1.53-1.45 (m, 1H), 1.42 (s, 9H),1.38-1.29 (m, 1H). LCMS. (M+H+) 528.2, (M+Na+) 550.1; (M-H)' 526.1.

Step 3. Préparation of Titie Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-piperidin-4-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide (hydrochloricsait)

Préparation of the titie compound from Intemediate 222(b) (100 mg) and 4.0 M HCl in dioxane (1mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, affordedthe titie compound (65.3 mg, 0.141 mmol) as a yellow powder in a combined yield of 90% forsteps 2 and 3. 1H NMR (d6-DMSO): δ 11.82 (s, 1H), 10.41 (s, 1H), 10.18 (s, 1 H), 9.16-9.00 (m, 1H), 8.93-8.73(m, 1H), 8.07 (s, 1H), 7.58 (s, 2H), 7.34-7.23 (m, 2H), 7.23-7.09 (m, 3H), 3.46-3.26 (m, 3H), 3.10-2.90 (m, 2H), 2.41-2.29 (m, 1H), 2.15-2.03 (m, 1H), 2.03-1.85 (m, 4H), 1.53-1.40 (m, 1H), 1.40-1.27 (m,1H). LCMS: (M+H+) 428.1, (M+Na+) 450.2; (M-H)’ 426.2. HRMS: (M+H+) calcd for C25H26N5O2, 428.2087, found 428.2086. 013017 227

Example_223:_(R)-2-Amino-2-cvclohexvl-A/-(6-oxo-2-piperidin-4-yl-5,6-dihvdro-1H- n.21diazepinof4.5.6-ccnindol-8-vh-acetamide: dihvdrochloride

Interrmediate 222(a),Example 222 ÛA„ ÊlHBoc

HATU, E^N, DMF

10 15 20

Step 1. Préparation of (R)- 4-[8-(2-fert-Butoxycarbonylamino-2-cyclohexyl-acetylamino)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/]indol-2-yl]-piperidine-1-cartX}xylic acid tert-butyl ester 223(a)

Préparation of intermediate 223(a) from Intermediate 222(a) of Example 222 (60 mg, 0.157mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (44.3 mg, 0.172 mmol), triethylamine(0.086 mL, 0.617 mmol), and 0-(7-azabenzotriazol-1-yl)-Af,/V,A/’,/V-tetramethyluronlumhexafluorophosphate (71.5 mg, 0.188 mmol) in /V,W-dimethylformamide (8.0 mL) was carried outanalogously to Example 11. The volatile components were removed in vacuo, and the resultingresidue was dissolved in methanol and loaded onto a silica gel plug. The plug was then loadedonto a silica gel column and eluted with 1:1 dichloromethane: ethyl acetate to afford Intermediate223(a) (107 mg) as a yellow solid contaminated with Λ/,/V-dimethylformamide which was carriedon directly to the next step. 1H NMR (d6-DMSO): δ 11.57 (s, 1H), 10.14 (st 1H), 10.03 (s, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.56(s, 1H), 7.54 (s, 1H), 6.85 (d, 1 H, J = 8.48 Hz), 4.15-3.99 (m, 2H), 3.99-3.85 (m, 1H), 2.92-2.76(m, 2H), 1.78-1.45 (m, 10H), 1.42 (s, 9H), 1.37 (s, 9H), 1.22-0.97 (m, 5H). LCMS: (M+H+) 623.2, (M+Na+) 645.2; (M-H)' 621.2.

Step 2. Préparation of Title Compound: (R)-2-Amino-2-cyclohexyl-A/-(6-oxo-2-piperidin-4-yl- 5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide; dihydrochloride

Préparation of the title compound from Intermediate 223(a) (100 mg, 0.161 mmol) and 4.0 M HClin dioxane (1.6 mL) was carried out analogously to Exemple 91. Isolation, also in an analogousmanner, afforded the title compound (63.2 mg, 0.128 mmol) as a yellow powder in a combinedyield of 82% for steps 1 and 2. 25 013017 228 1H NMR (dB-DMSO): δ 11.98 (s, 1H), 10.82 (s, 1H), 10.24 (s, 1H), 9.21-9.06 (m, 1H), 9.06-8.87 (m, 1 H), 8.35 (s, 3H), 8.04 (s, 1H), 7.64 (d, 1 H, J = 1.70 Hz), 7.60(s, 1H), 3.47-3.28 (m, 4H), 3.10-3.29 (m, 2H), 2.10-1.86 (m, 4H), 1.86-1.52 (m, 6H), 1.28-0.94 (m, 5H). LCMS: (M+H+) 423.2, (M+Na+) 445.1 ; (M-H)' 421.3. 5 HRMS: (M+H+) calcd for C23H3iN6O2, 423.2508, found 423.2492.

Example 224: (1.2-frans)-2-Pvridin-3-vl-cvclopropanecarboxvlic acid (6-oxo-2-piperidin-4-vl-5.6- dihvdro-1 H-ï 1,21diazepinoi4.5.6-cdlindol-8-vl)-amide: dihvdrochloride

Intermediate 222(a),Exemple 222'

4N HCl (Dioxane) CH2CI2, 99%

Step 1. Préparation of 4-{6-Oxo-8-[(1,2-irans)-(2-pyridin-3-yl-cyclopropanecarbonyl)-amino]- 10 5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cd]indol-2-yl}-piperidine-1-carboxylic acid fert-butylester 224(a)

Préparation of intermediate 224(a) from Intermediate 222(a) of Example 222 (60 mg, 0.157mmol), (1,2-frans)-2-pyridin-3’-yl-cyclopropanecarboxylic acid (40.2 mg, 75%, 0.172 mmol),triethylamine (0.086 mL, 0.617 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/\/,/V’,A/- 15 tetramethyluronium hexafluorophosphate (71.5 mg, 0.188 mmol) in /V,W-dimethylformamide (8.0mL) was carried out analogously to Example 11. The volatile components were removed in vacuo,and the resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plugwas then loaded onto a silica gel column and eluted with 25:1 dichloromethane: methanol toafford Intermediate 224(a) (59.2 mg, 0.112 mmol) as a yellow solid in 72% yield. 20 1H NMR (d6-DMSO): δ 11.59 (s, 1H), 10.39 (s, 1 H), 10.14 (s, 1H), 8.65 (d, 1H, J = 2.07 Hz), 8.53(dd, 1 H, J = 4.99, 1.41 Hz), 7.98 (d, 1 H, J = 1.70 Hz), 7.84 (d, 1 H, J = 7.91 Hz), 7.59-7.53 (m, 3H),4.16-4.02 (m, 3H), 2.95-2.74 (m, 2H), 2.22-2.13 (m, 1H), 1.78-1.45 (m, 7H), 1.42 (s, 9H). LCMS: (M+H+) 529.1 ; (M-H)’ 527.2. 013017 229

Step 2. Préparation of Titie Compound: (1,2-frans)-(2-Pyridin-3-yl-cyclopropanecarboxylicacid (6-oxo-2-piperidin-4-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide;dïhydrochloride

Préparation of the titie compound from Intermediate 224(a) (50 mg, 0.095 mmol) and 4.0 M HCl in5 dioxane (0.5 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, afforded the titie compound (47.4 mg, 0.095 mmol) as a yellow powder in 99% yield. 1H NMR (d6-DMSO): 5 11.87 (s, 1H), 10.59 (s, 1H), 10.20 (s, 1H), 9.18-9.00 (m, 2H), 8.89 (br s,2H), 8.72 (d, 1H, J = 5.09 Hz), 8.33 (d, 1H, J = 8.10 Hz), 8.07 (s, 1H), 7.96 (dd, 1H, J = 8.10, 7.72Hz), 7.60 (d, 2H, J = 5.09 Hz), 3.47-3.29 (m, 3H), 3.11-2.84 (m, 2H), 2.75-2.61 (m, 1H), 2.40-2.29 10 (m, 1H), 2.09-1.84 (m, 4H), 1.70-1.54 (m, 2H). LCMS: (M+H+)429.2, (M+Na+)451.1; (M-H)'427.1. HRMS: (M+H+) calcd for C24H25N6O2, 429.2039, found 429.2021.

Example 225: (1R.2R)-IV-(6-Oxo-2-Pvridin-4-vl-5,6-dihvdro-1H-(1,2)diazepinof4.5.6-cdlindol-8-v0- 2-phenvlcvclopropanecarboxamide 15

Intermediate 147(d),Example 147 4N HCl (Dioxane) -»- ch2ci2

HN-N

Step 1. Préparation of ferf-Butyl 6-oxo-2-pyridin-4-yl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-ylcarbamate 225(a) A mixture of Intermediate 147(d) of Example 147 (0.50 g, 1.3 mmol), 4-pyridyl boronic acid (0.25g, 2.0 mmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (106 mg, 0.13 mmol)and 3.0 M aqueous sodium carbonate (3.3 ml) in W,W-dimethy!formamide (20 ml) was stirred at 20 013017 230 100 °C for 4 hours. The volatile components were removed in vacuo and the residue wassubjected to on silica gel chromatography, eluting with CH2CI2:methanol (95:5 increasing to90:10). Intermediate 225(a) (0.41 g) was obtained in 82% yield. 1H NMR (ds-DIVISO): δ 12.22 (s, 1H), 10.52 (s, 1H), 9.60 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 7.855 (d, 1H, J= 1.7 Hz), 7.75 (d, 1H, J= 1.7 Hz), 7.60-7.72 (tn, 3H), 1.51 (s, 9H). LCMS (M++1):378.1

Step 2. Préparation of 8-Amino-2-pyridin-4-yi-1,5-dihydro-6ft-[1,2]diazepino[4,5,6-cd]indol-6-one hydrochloride 225(b) 10 To a mixture of Intermediate 225(a) (0.38 g, 1.0 mmol) in CH2CI2 (30 ml), was added 1M HCl indiethyl ether (20 ml). The mixture was then stirred at room température for 2 hours. The volatileswere removed in vacuo to provide Intermediate 225(b) which was carried' on directly to the nextstep without further purification.

Step 3. Préparation of Title Compound: (1R,2R)-/V-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1H- 15 [1,2]diazepino[4,5,6-cd|indol-8-yl)-2-phenylcyclopropanecarboxamide A solution of Intermediate 225(b) (ca. 0.5 mmol), (1 R,2R)-2-phenyl-cyclopropanecarboxylic acid(113 mg, 0.7 mmol), triethylamine (0.4 ml) and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) in 10 ml of Λ/,/V-dimethylformamidewas stirred at room température for 3 hours. The mixture was subjected to préparative HPLC to 20 afford the title compound (107 mg, 0.25 mmol) in 25% yield for steps 2 and 3. 1H NMR (d6-DMSO): δ 12.25 (s, 1H), 10.49 (s, 1H), 10.44 (s, 1H), 8.67 (s, 1H), 8,65 (s, 1H), 8.16(S, 1H), 7.48-7.91 (m, 4H), 7.20-7.46 (m, 2H), 6.96-7.20 (m, 3H), 2.26-2.40 (m, 1H), 1.94-2.13 (m, 1 H) 1.39-1.60 (m, 1H), 1.22-1.39 (m, 1H). HRMS calculated for C25H19N5O2 422.1617 (M+H), found 422.1626. 25 Example 226: /V-f6-Oxo-2-pyridin-4-yl-5.6-dihvdro-1/-/-f1,21diazepinoi4,5,6-cc1indol-8-v0-(1,2- frans)-2-pyridin-3-vlcvclopropanecarboxamide

30

Préparation of example 226 from Intermediate 147(d) of Example 147 (200 mg, 0.529 mmol) wascarried out anaiogously to the préparation of Example 225 in three steps except that (1,2-trans)-2-pyridin-3-yl-cyclopropanecarboxylic acid was used instead of (1R,2R)-2-phenyl- 013017 231 cyclopropanecarboxylic acid in step 3. isolation, also in an analogous manner, afforded the titlecompound (54 mg) as a yeliow powder in 25% yieid overall. 1H NMR (d6-DMSO): δ 12.26 (s, 1H), 10.49 (s, 1 H), 10.47 (s, 1 H), 8.67 (s, 1H), 8.65 (s, 1H), 8.46(s, 1 H), 8.30-8.43 (d, 1H, J = 4.7 Hz), 8.16 (s, 1H), 7.57-7.88 (m, 4H), 7.45-7.57 (m, 1H), 7.19- 5 7.41 (m, 1H), 2.32-2.42 (m, 1H), 2.01-2.20 (m, 1H), 1.46-1.65 (m, 1H), 1.32-1.46 (m, 1H). HRMS calculated for C24H18N6O2 423.1569 (M+H), found 423.1598.

Example 227. f2.9-Dichloro-6-oxo-5,6-dihvdro-1H-f1.21diàzepino|4,5.6-ctflindol-8-vD-carbamic acid ferf-butvl ester

Interrnediate 147(c),Exemple 147

NCS, DMF ->. 60 °C, 35%

HN—N

BocHN

10 15

To a solution of Interrnediate 147(c) of Exemple 147 (1.5 g, 5 mmol) in CHCI3 (10 mL) and N,N-dimethylformamide (15 mL), was added N-chlorosuccinimide (701 mg, 5.25 mmol). The mixturewas heated to 60 °C and stirred for 3 hours. Chloroform, W,W-dimethylformamide and water wereadded. Following extractive work-up with chloroform, the organic layer was dried over Na2SO4 andfiltered. Evaporation of the volatile components gave a deep brown residue to which methanolwas added. Filtration and collection of the solids gave the title compound (648 mg) as deep brownsolid whose purity by NMR and HPLC was estimated to be about 70%. 1H-NMR (d6-DMSO): δ 13.15 (s, 1H), 10.62 (s, 1H), 8.90 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 1.47(s, 9H). LCMS: (M+H+) 370.2. 20 013017 232

Exemple 228: (R)- 8-(2-Amino-2-cvclohexvl-acetylamino)-6-oxo-5.6-dihvdro-1H- f1,21diazepinof4,5,6-cdlindole-2-carboxylic acid (2-dimethvlamino-ethvh-amide: dihydrochloride

OA

Intennediate 171 (a), _NHBoc_

Example 171 EDCI. EfeN, 4-DMAP DMF.24%

Step 1. Préparation of (R)-{Cyclohexyl-[2-(2-dimethylaminQ-ethylcarbamoyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-ylcarbamoyIJ-methyl}-carbamic acid iert-butylester 228(a)

Préparation of intermediate 228(a) from Intermediate 171 (a) of Example 171 (200 mg, 0.571mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid , (147 mg, 0.571 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (131 mg, 0.686 mmol), and 4-dimethylaminopyridine (84 mg, 0.688 mmol) in W,W-dimethylformamide (8.0 mL) was carried outanalogously to Example 190, step 2. When the reaction was judged complété, the volatilecomponents were removed in vacuo, and the resulting residue was dissolved in methanol andloaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with40:3:0.3 dichloromethane: methanol: ammonium hydroxide to afford Intermediate 228(a) (77 mg,0.139 mmol) as a yellow solid in 24% yield. ’H NMR (d6-DMSO): δ 12.65 (s, 1H), 10.66 (s, 1H), 10.26 (s, 1H), 9.83 (brs, 1H), 8.98 (br s, 1H),8.16 (s, 2H), 7.76 (s, 1H), 6.93 (d, 1H, J = 9.23 Hz), 4.18-4.03 (m, 1H), 4.01-3.85 (m, 1H), 3.71-3.56 (m, 2H), 2.83 (s, OH), 1.78-1.45 (m, 6H), 1.37 (s, 9H), 1.21-0.93 (m, 5H). LCMS: (M+H+)554.2, (M+Na+) 576.1 ; (M-H)' 552.2.

Step 2. Préparation of Title Compound: (R)- 8-(2-Amino-2-cyclohexyl-acetyiamino)-6-oxo- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; dihydrochloride

Préparation of the title compound from Intermediate 228(a) (75 mg, 0.136 mmol) and 4.0 M HCl indioxane (1.36 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded the title compound (71.3 mg, 0.136 mmol) as a yellow powder in 99% yield. 1H NMR (d6-DMS0): δ 12.95 (s, 1H), 10.98 (s, 1H), 10.70 (s, 1H), 10.08 (br s, 1H), 9.16 (s, 1H),8.37 (s, 3H), 8.21 (s, 1H), 8.13 (d, 1H, J= 1.32 Hz), 7.79 (d, 1H, J = 1.51 Hz), 3.85-3.74 (m, 1H), 013017 233 3.65 (d, 2H, J = 5.84 Hz), 3.30 (d, 2H, J = 6.41 Hz), 2.83 (d, 6H, J = 4.71 Hz), 1.93-1.52 (m, 6H)1.29-0.97 (m,5H). LCMS: (M+H+) 454.2, (M+Na+) 476.1; (M-H)'452.1. HRMS: (M+H+) calcd for C23H32N7O3, 454.2567, found 454.2574.

Example 229: A/-(Cvclohexvlmethvl)-/V-(6-oxo-5,6-dihvdro-1 /7-[1,21diazepinoi4,5.6-ccnindol-8·

Préparation of example 229 from the title compound of Example 2 (25 mg, 0.11 mmol), Ν,Ν'-disuccinimidyl carbonate (27 mg, 0.11 mmol), /V,/V-diisopropylethylamine (0.024 mL, 0.21 mmol) 10 and 1-cyclohexylmethanamine (0.028 mL, 0.021 mmol) in A/./V-dimethyiformamide (1.0 mL) wascarried out analogously to Example 207. Purification, also in an analogous manner, afforded thetitle compound (4 mg, 0.009 mmol) as yellow powder in 8% yield. 1H NMR (CDCIa/methanol-dJ: δ 8.02 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 3.06 (d, 2H,J = 5.84 Hz), 1.82-1.71 (m, 5H), 1.34-1.18 (m, 5H), 0.97 (m, 1H). 15 LCMS: (M-H)' 338.1, (M+Na+) 362.1.

Example 230: (1R. 2R)-2-Phenvl-cvclopropanecarboxvlic acid (2-morpholin-4-vlmethvl-6-oxo-5,6- dihvdro-1H-i1.2ldiazepinor4,5.6-cdlindol-8-v0-amide compound with acetic acid

Title compoundof Example 164 1. K3Fe(CN)6, K2Os02(OH)4

K2CO3, THF, H2O ->. 2. NalO4, THF, H20,22%

Morpholine, NaBH(OAc)3--—>. HCl (Dioxane), THF, 71%

O;

H

1. 4N HCl (Dioxane)CH2CI2 2. HATU, Et3N, DMF, 31%

013017 234 . Step 1. Préparation of (2-Formyl-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(]indol-8-yl)-carbamic acid tert-butyi ester 230(a)

To a solution of the title compound of Example 164 (48 mg, 0.146 mmol) in 1:1tetrahydrofuran:H2O (4 mL) was added K2CO3 (30 mg, 0.219 mmol), K2OsO2(OH)4 (7 mg) and 5 K3Fe(CN)6 (72 mg, 0.219 mmol). The mixture was stirred at room température for 2 hourswhereupon water and ethyl acetate were added. Following extractive work-up, the organic layerwas then dried, filtered, and concentrated. The residue was dissolved in 1:1 tetrahydrofuran:H2O(2 mL) and sodium periodate (156 mg, 50.73 mmol) was added. The mixture was stirred at roomtempérature for 30 min whereupon water and ethyl acetate were added. Following extractive 10 work-up, the organic layer was then dried, filtered, and concentrated. Silica gel chromatography ofthe residue, eluting with 30% ethyl acetate in hexane gave Intermediate 230(a) as a pale yellowsolid (11 mg, 0.034 mmol) in 22% yield.

Step 2. Préparation of (2-Morpholin-4-ylmethyl-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-carbamic acid tert-butyi ester 230(b) 15 To a solution of morpholine (0.32 mL, 3.64 mmol) and powdered 4A molecular sieves (1.0 g) intetrahydrofuran (5 mL) was added 4M HCl in dioxane (0.91 mL; 3.64 mmol). After 10 min, asolution of Intermediate 230(a) (199 mg, 0.607 mmol) in tetrahydrofuran (2 mL) was addeddropwise followed by NaBH(OAc)3 (254 mg, 1.2 mmol). The resulting suspension was stirred atroom température for 24 hours. The mixture was quenched with saturated aqueous sodium 20 bicarbonate and filtered through diatomaceous earth, which was then washed with ethyl acetate.More ethyl acetate was added to the filtrate, and the aqueous layer was extracted. The combinedorganic layers were dried over Na2SO4, filtered, and concentrated. The residue was subjected tosilica gel chromatography eluting with 5 % MeOH/ethyl acetate to give Intermediate 230(b) as apale yellow powder (173 mg, 0.43 mmol) in 71 % yield. 25 ’H NMR (d6-DMSO): 11.71 (s, 1H), 10.21 (s, 1H), 7.73 (s, 1H), 7.62 (s, 2H), 3.74 (s, 2H), 3.63-3.61 (m, 4H), 2.43-2.41 (m, 4H), 1.52 (s, 9H). LCMS: (M+H+) 400.

Step 3. Préparation of Title compound: (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid (2-morpholin-4-ylmethyl-6-oxo-5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide 30 compound with acetic acid

Préparation of the title compound from intermediate 230(b) (173 mg, 0.433 mmol) in CH2CI2 (2mL) and 4M HCl in dioxane (2 mL) was carried out analogously to the préparation of Example 91.After concentration, the residue was dissolved in /V,/V-dimethylformamide (5 mL). (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid (84 mg, 0.52 mmol), triethylamine (0.18 mL, 1.3 mmol), and 35 0-(7-azabenzotriazol-1-yl)-/\/,/\/,/V’,/V-tetramethyluronium hexafluorophosphate (247 mg, 0.65mmol) were added. After 12 hours, the mixture was concentrated and subjected to préparative 013017 235 HPLC in a manner analogous to Example 146, Step 2. The title compound (59 mg, 0.13 mmol)was obtained as a pale yellow powder in 31 % yield. 1H NMR (dg-DMSO): 11.84 (s, 1H), 10.42 (s, 1H), 10.28 (s, 1H), 8.10 (s, 1H), 7.67 (s, TH), 7.64 (s,1H), 7.39-7.24 (m, 5H), 3.78 (s, 2H), 3.68-3.64 (m, 4H), 2.49-2.47 (m, 4H), 2.14 (m, 1K), 1.56 (m, 5 1H), 1.42 (m, 1H). LCMS: (M+H+) 444.1

Example 231 : /V-(6-Oxo-2-pyridin-3-vl-5.6-dihvdro-1 H-ï 1 ,21diazepinof4.5.6-cd]indol-8-vl)-f 1.2- frar?s)-2-pvridin-3-ylcvclopropanecarboxamide 10

Préparation of example 231 from Intermediate 147(d) of Example 147 was carried outanalogously to the préparation of Example 225 in three steps except that 3-pyridyl boronic acid 15 was used instead of 4-pyridyl boronic acid in step 1 and (1,2-frans)-2-pyridin-3-yl-cyclopropanecarboxylic acid was used instead of (1R,2R)-2-phenyl-cyclopropanecarboxyiic acid instep 3. Isolation, also in an analogous manner, afforded the title compound (69 mg) as a yellowpowder in 33% yield overall. 1H NMR (d6-DMSO): δ 12.19 (s, 1H), 10.30-10.50 (m, 2H), 8.81 (m, 1H), 8.60 (m, 1H), 8.46 (m, 20 1H), 8.36 (m, 1H), 8.13 (m, 1 H), 7.93-8.08 (m, 1H), 7.37-7.69 (m, 4H), 7.27 (m, 1H), 2.40 (m, 1H), 2.08 (m, 1H), 1.28-1.60 (m, 2H). HRMS calculated for C24H18N6O2 423.1569 (M+H), found 423.1590.

Example 232; (1R,2R)-A/-(6-Qxo-2-pvridin-3-vl-5,6-dihvdro-1H-f1,2ΚΙΐ3Ζ6ρΐηοί4.5,6-οά1ιηάθ1-8-νΒ- 2-ohenvlcvclopropanecarboxamide

Préparation of example 232 from Intermediate 147(d) of Example 147 was carried outanalogously to the préparation of Example 225 in three steps except that 3-pyridyl boronic acidwas used instead of 4-pyridyl boronic acid in step 1. Isolation, also in an analogous manner,afforded the title compound (18 mg) as a yellow powder in 8% yield overall. 01301 236 1H NMR (de-DMSO): § 12.18 (s, 1H), 10.28-10.54 (m, 2H), 8.81 (m, 1H), 8.60 (m, 1H), 8.13 (m,1H), 7.95-8.08 (m, 1H), 7.57-7.70 (m, 1H), 7.49-7.57 [m, 1 H), 7.38-7.48 (m, 1H), 7.01-7.34 (m,3H) 4.05 (m, 1H), 2.32 (m, 1 H), 2.03 (m, 1H), 1.46 (m, 1H), 1.32 (m, 1H). HRMS calculated for C25H19N5O2 422.1617 (M+H), found 422.1598.

Example 233: (1R.2R)- 2-Phenvl-cvclopropanecarboxvlicacid r2-(3-dimethvlamino-prop-1-vnvl)-6- oxo-5.6-dihvdro-1H-f1.2ldiazepinof4,5.6-cdlindol-8-vn-amide

Inteimediate 147(d),Example 147

Pd(PPh3)2CI2, Cul, ÎMGDMF, 90 °C, 43%

HN-N

BocHN

233(a)

Ah HATU, Et3N, DMF, 76%

HN-N

10 15

Step 1. Préparation of [2-(3-Dimethylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-l/7- [1,2]diazepino[4,5,6-cd]indol-8-yl]-carbamic acid fert-butyl ester 233(a)

Under argon atmosphère, dimethyl-prop-2-ynyl-amine (198 mg, 2.38 mmol),dichlorobis(triphenylphosphine)palladium(li) (27.6 mg, 0.039 mmol), copperl iodide (7.8 mg, 0.041mmol) and /V,/V,/V,/V-tetramethylguanidine (912 mg, 7.93 mmol) were added to a solution ofIntermediate 147(d) from Example 147 (300 mg, 0.794 mmol) in W,/V-dimethylformamide (3 mL)and dioxane (12 mL). The reaction was heated at 90 °C for 4 hours at which point the volatilecomponents were removed in vacuo. The resulting residue was dissolved in methanol and loadedonto a silica gel plug. The plug was then loaded onto a silica gel coiumn and eluted with 20:1:0.1dichloromethane: methanol: ammonium hydroxide to afford Intermediate 233(a) (130 mg, 0.341mmol) as a yellow solid in 43% yield. 1H NMR (d6-DMSO): δ 12.09 (s, 1H), 10.45 (s, 1H), 9.54 (s, 1H), 7.71 (s, 1H), 7.65 (d, 1H, J =1.51 Hz), 7.40 (s, 1H), 3.61 (s, 2H), 2.27 (s, 6H), 1.47 (s, 9H). LCMS: (M+H+) 382.1, (M+Na+) 404.1; (M-H)’ 380.1. 20

237

Step 2. Préparation of 8-Amino-2-(3-dimethylamino-prop-1-ynyl)-1,5-dihydro- [1,2]diazepino[4,5,6-cd|indol-6-one; dihydrochloride 233(b)

Préparation of intermediate 233(b) from Intermediate 233(a) (126 mg, 0.331 mmol) and 4M HCl indioxane (1.68 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner, afforded Intermediate 233(b) (117 mg, 0.331 mmol) as a yellow powder in 99% yield. 1H NMR (de-DMSO): δ 12.56 (brs, 1H), 10.68 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 4.46(s, 2H), 2.88 (s, 6H). LCMS: (M+Na+) 304.1 ; (M-H)' 280.1.

Step 3. Préparation of Title Compound: (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2- (3-dimettiylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-ylJ- amide

Préparation of the title compound from Intermediate 233(b) (110 mg, 0.312 mmol), (ÎR,2R)-2-phenyl-cyclopropanecarboxylic acid (55 mg, 0.339 mmol), triethylamine (0.189 mL, 1.36 mmol),and 0-(7-azabenzotriazol-1-yl)-/V,W,W',/V’-tetramethyluronium hexafluorophosphate (155 mg,0.408 mmol) in W,/V-dimethylformamide (10.0 mL) was carried out analogously to Example 11.The volatile components were removed in vacuo, and the resulting residue was dissolved inmethanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column andeluted with 40:3:0.3 dichloromethane: methanol: ammonium hydroxide to afford the titlecompound (100 mg, 0.235 mmol) as a yellow-brown soiid in 76% yield. ’H NMR (de-DMSO): δ 12.24 (s, 1H), 10.53 (s, 1H), 10.47 (s, 1H), 8.10 (d, 1H, J= 1.32 Hz), 7.62(d, 1H, J= 1.51 Hz), 7.45 (s, 1H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 3H), 3.84 (s, 2H), 2.44 (s, 6H),2.42-2.32 (m, 1H), 2.12-2.02 (m, 1H), 1.55-1.45 (m, 1H), 1.42-1.32 (m, 1H). LCMS: (M+H+) 426.0, (M+Na+) 448.1 ; (M-H)' 424.1. HRMS: (M+HT) calcd for C25H24N5O2, 426.1930, found 426.1911.

Example 234: (1R, 2R)-2-Phenyl-cvclopropanecarboxvlic acid f2-(4-methvl-piperazine-1-carbonyl)- 6-oxo-5,6-dihvdro-1/7-f1.2)diazepinof4,5.6-ccflindol-8-vl1-amide (acetic acid sait) 013017 238

Intermediate 147(d),Example 147

HN Z~\ ,NCH3

Pd(PPh3)4, CO, DMF, 50%

BocHN

H 234(a) 1. 4N HCl (Dioxane)

HN-N /—NCH*

CH2CI2 2. HATU, Et3N, DMF, 15%

Step 1. Préparation of [2-(4-Methyl-piperazine-1-carbonyl)-6-oxo-5,6-dihydro-1H- [1,2]diazepino[4,5,6-cd]indol-8-yI]-carbamic acid tert-butyl ester; compound with acetic 5 acid 234(a)

Préparation of intermediate 234(a) from Intermediate 147{d) of Example 147 (453 mg, 1.2 mmol),/V-methylpiperazine (0.66 mL, 6 mmol), and tetrakis(triphenylphosphine)palladium(0) (105 mg,0.09 mmol) in /V,/V-dimethylformamide (7 mL) was carried out analogously to the préparation ofExample 161 except that tetrakis(triphenylphosphine)palladium(0) was used as the catalyst 10 instead of bis(diphenylphosphino)ferrocenedichloropalladium (II). After concentration, the residuewas subjected to préparative HPLC (Peeke Scientific, Hl-Q C18 reverse phase 5u, 100A,250x21.2 mm column) eluting with CH3CN and 0.1% acetic acid in water at a flow rate of 20mL/min using a gradient of 5-95% CH3CN over 40 min to give Intermediate 234(a) (254 mg, 0.6mmol) as a pale green powder in 50% yield. 15 1H NMR (d6-DMSO): 12.06 (s, 1H), 10.46 (s, 1H), 9.52 (s, 1 H), 7.74 (s, 1 H), 7.64 (s, 1H), 7.37 (s,1H), 3.49-3.48 (m, 4H), 2.29-2.28 (m, 4H), 2.20 (s, 3H), 1.42 (ε, 9H). LCMS: (M+H+) 426.1

Step 2. Préparation bf Title compound: (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(4-methyl-piperazine-1 -carbonyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd|indol-8-yl]- 20 amide (acetic acid sait)

Préparation of the title compound from Intermediate 234(a) (445 mg, 1.06 mmol) in CH2CI2 (5 mL) and 4M HCl in dioxane (5 mL) was carried out analogously to Example 91. After concentration, the residue was dissolved in W,N-dimethylformamide (5 mL). (1R, 2R)-2-Phenyl- cyclopropanecarboxylic acid (162 mg, 1.0 mmol), triethylamine (0.42 mL, 3 mmol), and O-(7- 25 azabenzotriazol-1-yl)-W,/V,/V',/V-tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol) was 013017 239 sequentially added. After 12 hours, the mixture was concentrated. The crude product waspurified by préparative HPLC in a manner analogous to Example 146, Step 2, to give the titlecompound as a pale yellow powder (74 mg, 0.16 mmol) in 15% yield. 1H NMR (de-DMSO): 12.25 (s, 1 H), 10.59(s, 1H), 10.51 (s, 1 H), 8.18 (s, 1 H), 7.69 (s, 1 H), 7.49 (s,1 H), 7.34-7.19 (m, 5H), 3.63 (brs, 4H), 2.56 (s, 3H), 2.40-2.30 (m, 4H), 2.11 (m, 1H), 1.56 (m,1H), 1.42 (m, 1H). LCMS: (M+H+) 444.1

Example 235: (1R.2R)- 2-Phenvl-cvclopropanecarboxvlic acid f2-(3-dimethvlamino-propvl)-6-oxo- 5.6-dihvdro-1 /7-f 1,21diazepinof4,5,6-ccflindol-8-vll-amide

In a manner analogous to that of Example 183, 10% palladium on activated carbon (20 mg) wasadded to a solution of the title compound of Example 233 (20 mg, 0.047 mmol) in methanol (3mL). The reaction mixture was purged with Hz and stirred at room température under H2 (1 atm.)for 1 hour. The reaction mixture was loaded onto a silica gel plug. The plug was then loaded ontoa silica gel column and eluted with 20:1:0.1 dichloromethane: methanol: ammonium hydroxide toafford the title compound (8 mg, 0.0186 mmol) as a yellow solid in 40% yield. 1H NMR (d6-DMSO): δ 11.70 (s, 1H), 10.34 (s, 1H), 10.17 (s, 1H), 8.04 (d, 1 H, J= 1.51 Hz), 7.52(d, 1H, J= 1.51 Hz), 7.48 (s, 1H), 7.33-7.25 (m, 2H), 7.23-7.14 (m, 3H), 2.98-2.81 (m, 4H), 2.66(br s, 6H), 2.41-2.31 (m, 1H), 2.11-2.02 (m, 1H), 2.01-1.87 (m, 2H), 1.53-1.43 (m, 1H), 1.41-1.31(m, 1H). LCMS: (M+H+) 430.1, (M+Na+) 452.1; (M-H)' 428.1. HRMS: (M+H+) calcd for C25H2eN5O2, 430.2243, found 430.2240.

Example 236: (1R.2R)- 2-Phenvl-cvclopropanecarboxvlic acid f2-f3-dimethvlamino-propenvl)-6- oxo-5.6-dihvdro-1 /741.21diazepinor4.5.6-cdlindol-8-vn-amide H2, Lindlats Catalyst

Example 233 _> quinoline, MeOH, 66%

To a mixture of the title compound from Example 233 (45 mg, 0.106 mmol), Lindlar catalyst (45mg), and quinoline (4.1 mg, 0.032 mmol) was added anhydrous methanol (3 mL). The reactionmixture was purged with H2 and stirred at room température under H2 (1 atm) for 2.5 hours. Thereaction mixture was loaded onto a silica gel plug. The plug was then loaded onto a silica gelcolumn and eluted with 20:1:0.1 dichloromethane: methanol: ammonium hydroxide to afford thetitle compound (30 g, 0.070 mmol) as a yellow solid in 66% yield. 0130^ 240 1H NMR (d6-DMSO): δ 13.07 (s, 1 H), 10.41 (s, 1H), 10.32 (s, 1H), 8.11 (d, 1 H, J= 1.70 Hz), 7.57(s, 1H), 7.54 (d, 1H, J = 1.70 Hz), 7.33-7.25 (m, 2H), 7.23-7.14 (m, 3H), 6.88 (d, 1H, J = 12.25Hz), 5.91 (dt, 1H, J = 12.06, 6.22), 3.16 (d, 2H,J = 5.65 Hz), 2.42-2.33 (m, 1H), 2.28 (s, 6H), 2.12-2.03 (m, 1H), 1.53-1.44 (m, 1H), 1.41-1.31 (m, 1H). LCMS: (M+H+) 428.1, (M+Na*) 450.0; (M-H)' 426.0. HRMS: (M+H+) calcd for C25H26NSO2, 428.2087, found 428.2082.

Example 237: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid f2-(3-methvlamino-prop-1-vnvl)-6- oxo-5,6-dihvdro-1 H-f1.21diazepinof4.5,6-cdlindol-8-vll-amide (hvdrochloric sait)

Title Compoundof Example 206

4N HCl (Dioxane) - CH2CI2, 97%

HN-N

H-CI

Step 1. Préparation of (1R,2R)-Methyl-(3-{6-oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H-[t ,2]diazepino[4,5,6-cd]indol-2-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester 237(b)

Intermediate 237(a) was prepared by stirring methyl-prop-2-ynyl-amine (0.5 g, 7.23 mmol), di-fert-butyl dicarbonate (1.74 g, 7.97 mmol) and 2,6-dimethyl-pyridine (0.088 g, 0.72mmol) in anhydrousacetonitrile (10 mL) at room température for 16 hours. The solvent was evaporated and theresidue was subjected to silica gel chromatography eluting with ethyi acetate to affordIntermediate 237(a) (1 g, 5.91 mmol) as colorless oil in 82% yield. In a manner analogous to thatof Example 233, Step 1, under an argon atmosphère, intermediate 237(a) (66 mg, 0.39 mmol),dichlorobis(triphenylphosphine)palladium(ll) (4.6 mg, 0.0066 mmol), copperl iodide (1.2 mg,0.0063 mmol) and /V,/V,/\/,/\/-tetramethylguanidine (150 mg, 1.30 mmol) were added to a solutionof the title compound from Example 206 (55 mg, 0.13 mmol) in /V,/V-dimethylformamide (0.5 mL)and dioxane (2 mL). The reaction was heated at 90 °C for 3 hours at which point the volatilecomponents were removed in vacuo. The resulting residue was dissolved in methanol and loadedonto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 3:2dichloromethane:ethyl acetate to afford Intermediate 237(b) (20 mg, 0.039 mmol) as a yellow solidin 30% yield. 013017 241 1H NMR (d6-DMSO): δ 12.22 (s, 1H), 10.51 (s, 1H), 10.46 (s, 1H), 8.08 (d, 1 H, J= 1.51 Hz), 7.61(d, 1 H, J = 1.70 Hz), 7.41 (s, 1H), 7.33-7.25 (m, 2H), 7.22-7.15 (m, 3H), 4.37 (s, 2H), 2.90 (s, 3H),2.41-2.33 (m, 1H), 2.11-2.02 (m, 1H), 1.54-1.45 (m, 1H), 1.42 (s, 9H), 1.39-1.32 (m, 1H). LCMS: (M-H)’510.0. 5 Step 2. Préparation of Title Compound: (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide(hydrochloric sait)

Préparation of the title compound from Intermediate 237(b) (20 mg, 0.039 mmol) and 4.0 M HCl indioxane (0.5 mL) was carried out analogously to Exampie 91. Isolation, also in an analogous 10 manner afforded the title compound (17 mg, 0.038 mmol) as a yellow powder in 97% yield. 1H NMR (ds-DMSO): δ 12.37 (s, 1H), 10.59 (s, 1H), 10.55 (s, 1H), 9.30 (br s, 2H), 8.14 (s, 1H),7.65 (s, 1H), 7.58 (s, 1H), 7.36-7.24 (m, 2H), 7.24-7.12 (m, 3H), 4.27 (s, 2H), 2.66 (s, 3H), 2.41-2.29 (m, 1H, partial obscured), 2.17-2.03 (m, 1H), 1.56-1.44 (m, 1H), 1.43-1.31 (m, 1H). LCMS: (M-H)'410.1. 15 HRMS: (M+H+) calcd for Ca^NsOz, 412.1774, found 412.1768.

Example 238: (1.2-fra/7s)-2-Pvridin-3-vl-cvcloDropanecarboxvlic acid f2-i3-methvlamino-prop-1- vnvl)-6-oxo-5.6-dihvdro-1 H-f1,21diazepinor4.5.6-cdlindol-8-vn-amide: dihvdrochloride

Intermediate 20S(a),Example 206

Intermediate 237<a),Example 237

Pd(PPh3)2CI2, Cul, TMGDMF, 90 °C, 37%

4N HCl (Dioxane)---► CH2CI2, 85%

Step 1. Préparation of (1,2-trans)-2-Pyridin-3-yl-cyclopropanecarboxylic acid (2-bromo-6-20 oxo-5,6-difiydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-yl)-amide 238(a) 013017 242

Préparation of intermediate 238(a) from Intermediate 206(a) of Example 206 (120 mg, 0.38mmol), (1,2-irans)-2-pyridin-3-yl-cyclopropanecarboxylic acid (106 mg, c.a 0.487 mmol, purity c.a.75%), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (88 mg, 0.461 mmol), and 4-dimethylaminopyridine (56 mg, 0.459 mmol) in Λ/,/V-dimethylformamide (15.0 mL) was carried outanalogously to the préparation of Example 190, step 2. When the reaction was judged complété,the volatile components were removed in vacuo, the resulting residue was dissolved in methanoland ioaded onto a silica gel plug. The plug was then Ioaded onto a silica gel column and elutedwith 50:3 dichloromethane:methanol to afford Intermediate 238(a) (90 mg, 0.212 mmol) as ayellow solid in 56% yield. 1H NMR (d6-DMSO): δ 12.60 (s, 1H), 10.46 (s, 1H), 10.45 (s, 1H), 8.50 (d, 1H, J= 1.88 Hz), 8.40(dd, 1 H, J = 4.62, 1.41 Hz), 8.08 (d, 1 H, J =1.70 Hz), 7.60 (d, 1 H, J - 1.51 Hz), 7.56 (dt, 1H, J =7.96, 1.86 Hz), 7.32 (dd, 1H, J = 7.91, 4.90 Hz), 7.27 (s, 1H), 2.45-2.37 (m, 1H), 2.16-2.06 (m,1H), 1.57-1.49 (m, 1H), 1.49-1.40 (m, 1H). LCMS: (M-H)' 422.0, 424.0.

Step 2. Préparation of Methyl-(3-{6-oxo-8-[(2-pyridin-3-yl-cyciopropanecarbonyl)-amïno]- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/Jindol-2-yl}-prop-2-ynyl)-carbamic acid iert-butylester 238(b)

Under argon in a manner analogous to that of Example 233, step 1, Intermediate 237(a) ofExample 237 (54 mg, 0.32 mmol), dichlorobis(triphenylphosphine)palladium(ll) (3.7 mg, 0.0053mmol), copperl iodide (1.0 mg, 0.0053 mmol) and /V,A/,/V,W-tetramethylguanidine (122 mg, 1.06mmol) were added to a solution of Intermediate 238(a) (45 mg, 0.106 mmol) in N,N-dimethylformamide (1 mL) and dioxane (2 mL). The reaction was heated at 90 °C for 2 hours atwhich point the volatile components were removed in vacuo. The resulting residue was dissolvedin methanol and Ioaded onto a silica gel plug. The plug was then Ioaded onto a silica gel columnand eluted with 20:1:0.1 dichloromethane: methanol: ammonium hydroxide to afford Intermediate238(b) (20 mg, 0.039 mmol) as a yellow solid in 37% yield. 1H NMR (de-DMSO): δ 12.23 (s, 1H), 10.52 (s, 1H), 10.50 (s, 1H), 8.45 (br s, 1H), 8.08 (s, 1H),7.61 (s, 1H), 7.56 (d, 1H, J = 7.91 Hz), 7.41 (s, 1H), 7.35 (br s, 1H), 4.37 (s, 2H), 2.90 (s, 3H),2.45-2.38 (m, 1H, partial obscured), 2.16-2.07 (m, 1H), 1.59-1.49 (m, 1H), 1.50-1.44 (m, 1H,partial obscured), 1.42 (s, 9H), LCMS: (M+H4) 513.2, (M+Na4) 535.1; (M-H)'511.1.

Step 3. Préparation of Title Compound: (1,2-frans)-2-Pyridin-3-yl-cyclopropanecarboxylicacid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-y|]-amide; dihydrochloride 243

Préparation of the titie compound from Intermediate 238(b) (20 mg, 0.039 mmol) and 4M HCl indioxane (0.5 mL) was carried out analogously to Example 91. Isolation, also in an analogousmanner afforded the titie compound (16 mg, 0.033 mmol) as a dark red solid in 85% yield. 1H NMR (de-DMSO): δ 12.46 (s, 1H), 10.77 (s, 1H), 10.59 (s, 1H), 9.46 (br s, 2H), 8.90 (s, 1H), 5 8.76 (d, 1H, J = 3.77 Hz), 8.34 (d, 1H, J = 7.35 Hz), 8.11 (s, 1H), 8.03-7.90 (m, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 4.25 (s, 2H), 2.65 (s, 3H), 2.49 (m, 1H, obscured), 2.41-2.29 (m, 1H, partialobscured), 1.73-1.55 (m, 2H). LCMS: (M-H)'411.1. HRMS: (M+H+) calcd for C23H21N6O2,413.1726, found 413.1753. 10 Example 239: (2R)-2-Amino-2-cvclohexvl-/V-f2-(3-methvlamino-prop-1-vnvO-6-oxo-5,6-dihvdro-1 H- H.21diazepinol4,5.6-cd|indol-8-vl1-acetamidede; dihvdrochtoride ox HN-N NHBoc 239(a) Intermediate 206(a),Example 206 ÊlHBoc - EDC, 4-DMAP, DMF, 30% HN—N 0« Intermediate 237(a), Example 237 Π 5 ί TV — 4N HCl (Dioxane) Pd(PPti3)2CI2, Cul.TMG ÊlHBoc H CH2CI2,11% DMF, 90 °C 239(b)

Step 1. Préparation of (RH(2-Bramo-6-oxo-5,6-dihydro-1W-[1,2]diazepino[4,5,6-cdJindol-8-ylcarbamoyl)-cyclohexyl-methyl]-carbamic acid iert-butyl ester 239{a) 15 Préparation of intermediate 239(a) from Intermediate 206(a) of Example 206 (120 mg, 0.38mmol), (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (120 mg, 0.466 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (87 mg, 0.455 mmol), and 4-dimethylaminopyridine (56 mg, 0.459 mmol) in /V,/V-dimethylformamide (7.0 mL) was carried outanalogously to the préparation of Example 190, step 2. When the reaction was judged complété, 20 the volatile components were removed in vacuo, and the resulting residue was dissolved inmethanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and 013017 244 eluted with 1.2:1 dichloromethane: ethyl acetate to afford Intermediate 239(a) (60 mg, 0.116mmol) as a yellow solid in 30% yield. 1H NMR (de-DMSO): δ 12.59 (s, 1H), 10.46 (s, 1 H), 10.14 (s, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.27(ε, 1H), 6.90 (d, 1H, J = 8.85 Hz), 3.91 (t, 1H, J= 8.29 Hz), 1.76-1.44 (m, 6H), 1.37 (s, 9H), 1.20-0.93 (m,5H). LCMS: (M-H)'518.0, 516.0.

Step 2. Préparation of (R)-{3-[8-(2-fert-Butoxycarbonylamino-2-cyclohexyl-acetylamino)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc(]indol-2-yl]-prop-2-ynyl}-methyl-carbamic acidfert-butyl ester 239(b)

Under an argon atmosphère in a manner analogous to that of Example 233 step 1, Intermediate237(a) of Example 237 (65 mg, 0.38 mmol), dichlorobis(triphenylphosphine)palladium(ll) (4.5 mg,0.0064 mmol), copperl iodide (1.2 mg, 0.0063 mmol) and A/,/V,/V,/V-tetramethylguanidine (146 mg,1.27 mmol) were added to a solution of Intermediate 239(a) (66 mg, 0.127 mmol) in N,N-dimethylformamide (0.5 mL) and dioxane (2 mL). The reaction mixture was heated at 90 °C for 3hours at which point the volatile components were removed in vacuo. The resulting residue wasdissolved in methanol and loaded onto a siiica gel plug. The plug was then loaded onto a silica gelcolumn and eluted with 4:1 dichloromethane: ethyl acetate to afford Intermediate 239(b) (10 mg)as a yellow solid contaminated with an unknown impurity. LCMS: (M+H+) 607.2, (M+Na+) 629.3; (M-H)' 605.2.

Step 3. Préparation of Titie Compound: (2R)-2-Amino-2-cyclohexyl-W-[2-(3-methylamino-prop-1 -ynyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamidede;dihydrochioride

Préparation of the titie compound from Intermediate 239(b) (10 mg) and 4 M HCl in dioxane (0.5mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, includeda further trituration with CH2CI2 which removed the impurity carried along from step 2. The titiecompound (6 mg, 0.013 mmol) was obtained as a yellow powder in a combined yield of 11% forsteps 2 and 3. ’H NMR (ds-DMSO): δ 12.52 (s, 1H), 10.90 (s, 1H), 10.66 (s, 1H), 9.37 (brs, 2H), 8.33 (brs, 3H),8.08 (s, 1H), 7.73 (d, 1H, J = 0.9 Hz), 7.61 (s, 1H), 4.27 (s, 2H), 3.84-3.74 (m, 1H), 2.67 (s, 3H),1.90-1.54 (m, 6H), 1.27-0.97 (m, 5H). LCMS: (M+Na+) 429.2; (M-H)' 405.2. HRMS: (M+H+) calcd for C^H^NgOa, 407.2195, found 407.2209.

Example 240: (1,2-frans)-/V-f1-(2-Hydroxvethvl)-6-oxo-5.6-dihvdro-1H-f1,21diazepinof4.5,6- cdlindol-8-vl1-2-phenylcvclopropanecarboxamide 013017 245

Intermediate 2(b),Example 2

HATU, EtgN, DMF, 74%

MeO. >0

methyl bromoacetate

K2CO3, DMF, 80 °C 79% 240(a)

5 Step 1. Préparation of Methyl 6-{[(2-phenylcyclopropyl)carbonyl]amino}-1H-indole-4-carboxylate 240(a)

Préparation of intermediate 240(a) from Intermediate 2(b) of Example 2 {2.27 g, 10 mmol), (1,2-frans)-2-phenyl-cyclopropanecarboxylic acid (1.79 g, 11 mmol), triethylamine (3.0 g, 30 mmol),and O-(7-azabenzotriazol-1-yl)-/V,/V,tV’,/V'-tetramethyluronium hexafluorophosphate (4.18 g, 11 10 mmol) in Λ/,/V-dimethylformamide (20 mL) was carried out analogously to Example 11.

Extractive work-up from ethyl acetate, followed by purification on silica gel column eluting withCH2CI2/ ethyl acetate afforded Intermediate 240(a) (2.47 g) in 74% yield. 1H NMR (ds-DMSO): 5 11.39 (s, 1H), 10.39 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.10-7.40 (m, 5H), 6.86 (s, 1H), 3.89 (s, 3H), 2.33-2.48 (m, 1H), 2.04-2.21, (m, 1 H), 1.46-1.63 (m, 1 H), 15 1.29-1.45 (m, 1 H). LCMS (M+H): 335.1.

Step 2. Préparation of Methyl 1-(2-methoxy-2-oxoethyl}-6-{[(2- phenylcyclopropyl)carbonyl]amino}-1 H-indole-4-carboxylate 240(b) 013017 246

Intermediate 240(a) (2.40 g, 7.2 mmol), methyl bromoacetate (1.32 g, 8.6 mmol) and K2CO3 (2.0g, 14.4 mmol) were mixed in /V,/V-dimethylformamide (25 mL) and stirred at 80 °C for 3 hours.After filtration the filtrate was evaporated, and the residue was subjected to silica gelchromatography eluting with CH2CI2/ethyl acetate to afford Intermediate 240(b) (2.31 g) in 79 %yield. 1H NMR (de-DMSO): δ 10.50 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.48 (m, 1 H), 7.10-7.38 (m, 5H), 6.90 (m, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.70 (s, 3H), 2.30-2.44 (m, 1H), 2.03-2.21 (m, 1H), 1.44-1.58 (m, 1H), 1.30-1.43 (m, 1H). LCMS (M+H): 407.1.

Step 3. Préparation of Methyl 1-(2-hydroxyethyl)-6-{[(2-phenylcyciopropyl)carbonyI]amino}-1tf-indole-4-carboxylate 240(c)

To Intermediate 240(b) (2.0 g, 49 mmol) in 1:1 ethanoktetrahydrofuran (80 mL) was added NaBH4(2.0 g, 53 mmol). The mixture was stirred at room température ovemight. Purification by silica gelchromatography afforded Intermediate 240(c) (0.85 g) in 46% yield. ’H NMR (de-DMSO): § 10.45 (s, 1H), 8.27 (s, 1H), 7.89 (d, 1H, J = 1.7 Hz), 7.49 (d, 1H, J = 1.5Hz), 7.15-7.35 (m, 5H), 6.87 (d, 1H, J = 3.0 Hz), 4.95 (t, 1H. J = 5.2 Hz), 4.20 (t, 2H, J = 5.7 Hz), 3.91 (s, 3H), 3.60-3.80 (m, 2H), 2.33-2.46 (m, 1H), 2.05-2.18 (m, 1H), 1.43-1.65 (m, 1H), 1.30-1.43 (m, 1H). LCMS (M+H): 379.1.

Step 4. Préparation of Title Compound: (1,2-irans)-/V-[1-(2-Hydroxyethyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino(4,5,6-crf|indol-8-yl]-2-phenylcyclopropanecarboxamide

With stirring, Intermediate 240(c) in Λ/,/V-dimethylformamide (7 ml) was added to a mixture ofPOCI3 (0.6 ml) and Λ/,/V-dimethylformamide (5 mL) at 0 °C. After 1 hour, the reaction wasquenched with water and extracted with ethyl acetate. The organic phase was dried with Na2SO4and filtered. After évaporation of the volatile components, the residue was mixed with methanol(50 ml) containing hydrazine (1 mL) and refluxed for 5 hours. After the mixture was cooled toambient température, and the resulting yellow precipitate was collected by filtration and washedwith methanol to afford the title compound (0.37 g) in 43% yield. ’H NMR (d6-DMSO): δ 10.41 (s, 1H), d10.25 (s, 1H), 8.12 (d, 1H, J = 1.6 Hz), 7.55 (s, 2H), 7.45(s, 1H), 7.10-7.33 (m, 5H), 4.12 (t, 2H, J = 5.1 Hz), 3.67 (t, 2H, J = 5.2 Hz), 2.29-2.40 (m, 1H),1.99-2.10 (m, 1H), 1.41-1.52 (m, 1H), 1.28-1.39 (m, 1H). HRMS calculated for C2ZH21N5O3 389.1614 (M+H), found 389.1627.

Example 241: (1R, 2R)-2-Phenvl-cvclopropanecarboxvlic acid (2-hvdroxvmethvl-6-oxo-5,6- dihvdro-1 H-f1.2-cc/|diazepinof4.5.61indol-8-vl)-amide 013017 247

Intermediate 230(a),

Example 230

H 241(a)

1. NaBH4, MeOH

HN-N 0=/

Step 1. Préparation of (2-Hydroxymethyl-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yI)-carbamic acid tert-butyl ester 241(a) 5 A solution of intermediate 230(a) of Example 230 (26 mg, 0.079 mmol) in methanol (2 ml_) wastreated with NaBH4 (6 mg, 0.16 mmol) at 0 °C for 15 min. The solution was quenched withsaturated aqueous NH4CI and diluted with ethyl acetate. After extraction, the organic phase waswashed with brine, dried (Na2SO4), fïltered, and concentrated. Silica gel chromatography of theresidue (3:1 ethyl acetate:hexane) gave intermediate 241(a) (13 mg) in 50% yield. 10 Step 2. Préparation of Title compound: (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid (2-hydroxymethyl-6-oxo-5,6-dihydro-1 H-[\ ,2-ccQdiazepino[4,5,6]indol-8-yl)-amideTo a suspension of Intermediate 241(a) (76 mg, 0.23 mmol) in CH2CI2 (2 mL) was added 4M HClin dioxane (2 mL, δ mmol). After stirring at room température for 2 hours, the mixture wasconcentrated and the residue was dissolved in /V,/V-dimethylformamide (2 mL). (1R,2R)-2-Phenyl- 15 cyclopropanecarboxylic acid (33.6 mg, 0.21 mmol), triethylamine (0.1 mL, 0.69 mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,W’,/V-tetramethyluronium hexafluorophosphate (131 mg, 0.345 mmol)were added. After stirring at room température for 2 hours, the mixture was concentrated and theresidue was subjected to préparative HPLC in a manner analogous to Example 146, step 2. Thetitle compound was obtained as a pale yellow powder (9 mg, 0.024 mmol) in 10% yield. 20 1H NMR (d6-DMSO): δ 11.79 (s, 1H), 10.36 (s, 1H), 10.19 (s, 1H), 8.05 (d, 1H, J= 1.88 Hz), 7.57(s, 1H), 7.56 (s, 1H), 7.32-7.19 (m, 5H), 5.70 (t, 1H, J = 4.0 Hz), 4.70 (d, 2H, J= 5.4 Hz), 2.35 (m,1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.36 (m, 1H). LCMS: (M+H+) 375.2 013017 248

Example 242: (1R.2R)- 2-Phenyl-cvclopropanecarboxylic acid (1-i2-(1,3-dioxo-1,3-dihydro- isoindol-2-vl)-ethyn-6-oxo-5.6-dihydro-1/-/-n,2ldiazepinof4,5.6-ccflindol-8-vl}-amide

10 15

The title compound of Example 100 (130 mg, 0.38 mmol), 2-(2’-bromo-ethyl)-isoindole-1,3-dione(0.48 g, 1.9 mmol) and K2CO3 (0.28 g, 2.0 mmol) were stirred in W,W-dimethylformamide (6 ml_) at80 °C for 20 hours. After évaporation of the volatile components, the residue was subjected tosilica gel chromatography eluting with CH2CI2/MeOH to afford the title compound (130 mg) in 67%yield. ’H NMR (d6-DMSO): δ 10.33 (s, 1H), 10.31 (s, 1H), 8.07-8.15 (d, 1K, J= 1.5 Hz), 7.72-7.85 (m,4H), 7.58 (s, 1H), 7.46-7.53 (d, 1H, J= 1.5 Hz), 7.40 (s, 1H), 7.27-7.37 (m, 2H), 7.12-7.27 (m,3H), 4.41 (t, 2H, J = 4.7 Hz), 3.95 (t, 2H, J = 4.9 Hz), 2.31-2.42 (m, 1H), 1.96-2.07 (m, 1H), 1.43-1.55 (m, 1H), 1.30-1.42 (m, 1H). HRMS calculated for C3oH24N504 518.1828 (M+H), found 518.1852.

Example 243: (1 R.2R)-2-Phenyl-cvclopropanecarboxvlic acid (2-dimethvlaminomethvl-6-oxo-5,6- dihvdro-1 /7-11,2ldiazepinof4.5.6-cdiindol-8-yl)-amide

Intermediate 230(a),Example 230

Morpholine, NaBH(OAc)3 -,-> HCl (Dioxane), THF, 15%

1. 4N HCl (Dioxane)CH2CI2

H 2. HATU, EfeN, DMF, 90%

0130Π 249

Step 1. Préparation of (2,2-Dimethylaminomethyl-6-oxo-5,6-dihydro-1W- [1,2]diazepino[4,5,6-c£/Jindol-8-yl)-carbamic acid tert-butyl ester 243(a)

Préparation of intermediate 243(a) from Intermediate 230(a) of Example 230 (707 mg, 2.16mmol), 2M dimethylamine in tetrahydrofuran (5.4 mL, 10.8 mmol), 4M HCl in dioxane (10.8 mL;10.8 mmol) and NaBH(OAc)3 (2.29 g, 10.8 mmol) in tetrahydrofuran (5 mL) with powdered 4Amolecular sieves (400 mg) was carried out analogously to Example 230, step 2. Silica gelchromatography (eluted with 2% methanol in CH2CI2), also in an analogous manner, affordedIntermediate 243(a) a pale yellow powder (112 mg, 0.31 mmol) in 15% yield.

Step 2. Préparation of Title compound: (1R,2R)-2-Phenyl-cyclopropanecarboxyiic acid (2-d imethylaminomethyl-6-oxo-5,6-dihyd ro-1 H-[1,2]diazepino[4,5,6-cdJ indoI-8-yl)-amidePréparation of the title compound from Intermediate 243(a) (112 mg, 0.31 mmol) was carried outanalogously to step 3 of Example 230. Silica gel chromatography (eluted with 2% methanol inethylacetate), also in an analogous manner, afforded the title compound (113 mg, 0.28 mmol) asa yellow powder in 90% yield. ’H NMR (de-DMSO): 11.84 (s, 1H), 10.38 (s, 1H), 10.28 (s, 1H), 8.75 (d, J = 4 Hz, 1H), 8.53 (d, J= 4 Hz, 1H), 8.07 (s, 1H), 7.62 (s, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.32-7.18 (m, 3H), 3.31 (s, 2H),2.49 (s, 6H), 2.33 (m, 4H), 2.09 (m, 1H), 1.50 (m, 1H), 1.36 (m, 1H). LCMS: (M-H)’400.

Example 244: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid f1-(2-amino-ethyn-6-oxo-5.6- dihvdro-1W1.21diazepinof4,5.6-cdlindol-8-vl1-amide; compound with acetic acid

The title compound of Example 242 (92 mg, 0.18 mmol) and hydrazine (0.2 ml) were refluxedtogether in éthanol (14 mL) 3 hours. After évaporation of the volatile components, the residue wassubjected to préparative HPLC which afforded the title compound (71.4 mg) as an acetic acid saitin 89% yield. 1H NMR (ds-DMSO): 8 10.44 (s, 1H), 10.27 (s, 1H), 8.15 (s, 1 H), 7.58 (s, 1H), 7.56 (s, 1H), 7.46(s, 1H), 7.26-7.34 (m, 2H), 7.12-7.23 (m, 3H), 3.99-4.13 (m, 2H), 2.88 (m, 2H), 2.33-2.42 (m, 1H),2.02-2.12 (m, 1H), 1.43-1.55 (m, 1H), 1.30-1.41 (m, 1H). HRMS calculated for C22H22N5O2 388.1774 (M+H), found 388.1797.

Example 245: 2-Naphthaien-1-vl-ethanesulfonic acid (6-oxo-5.6-dihvdro-1H-f1.2tdiazepinoî4,5.6- cdlindol-8-vl)-amide 013017 250

HN-N

Under nitrogen, the title compound of Example 2 (260 mg, 1.1 mmol), 2-(1-naphthyl)ethanesulphonyl chloride (300 mg, 1.18 mmol), and triethylamine (0.68 mL, 4.89 mmol)were refluxed in tetrahydrofuran (5 mL) for 12 hours. The volatile components were evaporatedand silica gel chromatography (eluted with 2% methanol in CH2CI2) of the residue afforded the titlecompound (61 mg, 0.15 mmol) as a yellow powder in 13% yield. 1H NMR (DMSO): δ 11.58 (s, 1H), 10.13 (s, 1H), 9.85 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (dd, J= 8.0, 4.0 Hz, 1H), 7.43-7.17 (m, 8H), 7.06 (m, 1H), 3.22-3.15 (m, 4H). LCMS: (M+H+) 417.0.

Example 246: (1R.2R)-2-Phenvl-cyclopropanecarboxylic acid f2-f3-morpholin-4-vl-prop-1-vnyl)-6- oxo-5,6-dihydro-1 /7-f1.21diazepinof4.5.6-cdlrndol-8-vn-amide

Préparation of example 246 from Intermediate 147(d) of Example 147 (300 mg, 0.794 mmol) wascarried out in three steps in a manner similar to that described for the préparation of Example 233except that 4-prop-2-ynyl-morpholine was used instead of dimethyl-prop-2-ynyl-amine in step 1. 4-Prop-2-ynyi-morpholine was prepared by refluxing 3-bromo-propyne, morpholine and K2CO3 intetrahydrofuran for 1 hour. The title compound (34 mg, 0.073 mmol) was obtained as a yellowpowder in 18% overall yield. ’H NMR (d6-DMSO): δ 12.21 (s, 1H), 10.49 (s, 1H), 10.46 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 7.41(s, 1H), 7.33-7.24 (m, 2H), 7.23-7.13 (m, 3H), 3.66 (s, 2H), 3.62 (br s, 4H), 2.54 (br s, 4H), 2.42-2.33 (m, 1 H), 2.11-2.02 (m, 1H), 1.54-1.44 (m, 1H), 1.42-1.32 (m, 1H). LCMS: (M+H+) 468.2, (M+Na+) 490.1 ; (M-H)' 466.1. HRMS: (M+H+) calcd for C27H26N5O3, 468.2036, found 468.2049. 013017

Example 247: (1R,2R)-2-Phenvl-cvclopropanecarboxvlic acid i6-oxo-2-(3-pyrrolidin-1-vl-prop-1- vnvl)-5.6-dihvdro-1H-f1,21diazepinor4,5,6-cdlindol-8-vll-amide 251

Préparation of exampie 247 from Intermediate 147(d) of Example 147 (300 mg, 0.794 mmol) wascarried out in three steps in a manner similar to that described for the préparation of Example 233except that 1-prop-2-ynyl-pyrrolidine was used instead of dimethyl-prop-2-ynyl-amine in step 1.1-Prop-2-ynyl-pyrrolidine was prepared by stirring 3-bromo-propyne, pyrrolidine and triethylamine atroom température in tetrahydrofuran for 2 hours. The title compound (80 mg, 0.177 mmol) wasobtained as a yellow powder in 36% overail yield. 1H NMR (de-DMSO): δ 12.18 (s, 1H), 10.48 (s, 1H), 10.45 (s, 1H), 8.07 (d, 1 H, J = 1.77 Hz), 7.61(d, 1H, J = 1.52 Hz), 7.39 (s, 1H), 7.32-7.25 (m, 2H), 7.23-7.14 (m, 3H), 3.75 (s, 2H), 2.60 (br s,4H), 2.41-2.33 (m, 1H), 2.10-2.03 (m, 1 H), 1.73 (brs, 4H), 1.52-1.46 (m, 1H), 1.40-1.33 (m, 1H).LCMS: (M+H+) 452.1, (M+Na+) 474.1 ; (M-H)' 450.2. HRMS: (M+H+) calcd for C27H26N5O2, 452.2087, found 452.2102.

Example 248: (1R.2R)-2-Phenyl-cvclopropanecarboxvlic acid f1-(2-amino-ethvl)-2-chloro-6-oxo- 5,6-dihvdro-1 H-11.21diazepinof4.5.6-cdlindol-8-vn-amide

Préparation of example 248 was carried out two steps. The first step was carried out in a manneridentical to that described for the préparation of Example 242 except that the title compound ofExample 190 was used instead of the title compound of Example 100. This gave the phthaloylprotected intermediate. The second step consisted of phthaloyl deprotection, and the conditionswere identical to those described in Example 244. Purification, analogous to that described forExampie 244, gave the title compound (0.054 g) as a yellow powder in 49% overail yield. 1H NMR (d6-DMSO): δ 10.55 (s, 1H), 10.53 (s, 1H), 8.22 (s, 1 H), 8.00-8.18 (br d, 2H), 7.57 (s,1H), 7.36 (s, 1 H), 7.19-7.29 (m, 2H), 7.05-7.18 (m, 3H), 4.39 (t, 2H, J = 6.6 Hz), 3.06 (t, 2H, J =6.5 Hz), 2.28-2.37 (m, 1H), 2.00-2.13(m, 1H), 1.39-1.51 (m, 1H), 1.26-1.38 (m, 1H). HRMS calculated for C^H^NgOj 422.1384 (M+H), found 422.1403. 013017

Example 249: 1.2,3.4-Tetrahydro-naphthalene-2-carboxvlic acid (6-oxo-5,6-dihydro-1/-if- f1.2ldiazepinol4.5.6-cdlindol-8-vl)-amide 252

HN—N

Préparation of exampie 249 from the tifcle compound of Example 2 (freebase) (100 mg, 0.500mmol), 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (100 mg, 0.567 mmol), triethylamine(0.278 mL, 2.00 mmol), and O-(7-azabenzotriazol-1-yl)-W,/V,/V',/V-tetramethyluroniumhexafluorophosphate (285 mg, 0.750 mmol) in /V,/V-dimethylformamide (4.0 mL) was carried outanalogously to Example 11. Silica gel chromatography (eluted with ethyl acetate), also in ananalogous mariner, afforded the title compound (87 mg, 0.243 mmol) as a yellow powder in 48%yield. 1H NMR (d6-DMSO): δ 11.73 (d, 1H, J = 2.26 Hz), 10.23 (s, 1H), 10.11 (s, 1H), 8.16 (d, 1H, J =1.51 Hz), 7.60 (d, 1H, J = 1.70 Hz), 7.55 (d, 1H, J = 2.64 Hz), 7.46 (s, 1H), 7.14-7.06 (m, 4H),2.97-2.88 (m, 2H), 2.86-2.70 (m, 3H), 2.14-2.02 (m, 1H), 1.86-1.68 (m, 1H). LCMS: (M+H+) 359.1, (M+Na+) 381.0; (M-H)‘ 357.2. HRMS: (M+H+) calcd for C21H19N4O2, 359.1481, found 359.1484.

Anal. Calcd. for C2,H18N4O2: C, 70.38; H, 5.06; N, 15.63.

Found: C, 69.36; H, 5.07; N, 15.21.

Example 250: 2-f4-Chloro-phenvlsulfanvl1-A/-(6-oxo-5,6-dihvdro-1/-j-i1.2ldiazepinof4.5.6-ccflindol- 8-vl)-acetamide

HN-N

Préparation of example 250 from the title compound of Example 2 (freebase) (100 mg, 0.500mmol}, (4-chloro-phenylsulfanyl)-acetic acid (110 mg, 0.543 mmol), triethylamine (0.278 mL, 2.00mmol), and O-(7-azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium hexafluorophosphate (285mg, 0.750 mmol) in Λ/,/V-dimethylformamide (4.0 mL) was carried out analogously to Example 11.When the reaction was judged complété, the /V,/V-dimethylformamide was evaporated andmethanol was added. The mixture was filtered to collect the solids, which were then washed withmethanol, dichloromethane and diethyl ether. After drying under vacuum, the title compound (115mg, 0.321 mmol) was obtained as a yellow powder in 72% yield. 1H NMR (d6-DMSO): δ 11.73 (d, 1H, J = 1.70 Hz), 10.35 (s, 1H), 10.26 (s, 1H), 8.06 (d, 1H, J =1.51 Hz), 7.56 (d, 1H, J = 2.64 Hz), 7.52 (d, 1 H, J = 1.51 Hz), 7.48-7.34 (m, 5H), 3.86 (s, 2H). 013017 253 LCMS: (M-H)’ 383.0. HRMS: (M+H+) caicd for C18H14CIN4O2S, 385.0526, found 385.0538.

Anal. Calcd. for C18H53CIN4O2S 0.25 CH3OH: C, 55.79; H, 3.59; N, 14.26; Cl, 9.02.

Found: C, 55.49; H, 3.65; N, 14.57, Cl, 8.87. 5 Example 251: 2-(4-Chloro-phenyl)-A/-(6-oxo-5,6-dihydro-1H-f1.21diazepinor4.5.6-ccflindol-8-vl)- acetamide

Préparation of example 251 from the title compound of Example 2 (106 mg, 0.448 mmol), (4-chloro-phenyl)-acetic acid (85.0 mg, 0.498 mmol), triethylamine (0.313 mL, 2.25 mmol), and O-(7- 10 azabenzotriazol-1-yl)-A/,W,Af,W-tetramethyluroniurn hexafluorophosphate (257 mg, 0.676 mmol) inN,W-dimethylformamide (4.0 mL) was carried out analogously to Example 11. Silica gelchromatography (eluted with 1:1 ethyl acetate: hexane), also in an analogous manner, affordedthe title compound (130 mg, 0.369 mmol) as a yellow powder in 82% yield. 1H NMR (d6-DMSO): δ 11.73 (d, 1H, J = 1.70 Hz), 10.31 (s, 1H), 10.24 (s, 1H), 8.10 (d, 1H, J = 15 1.51 Hz), 7.57-7.53 (m, 2H), 7.45 (S, 1H), 7.37 (ddd, 4H, J = 8.67, 8.67, 2.64 Hz), 3.64 (s, 2H). LCMS: (M+H+) 353.2; (M-H)' 351.2.

Anal. Calcd. for C18H13CIN4O2: C, 61.28; H, 3.71; N, 15.88; Cl, 10.05.

Found: C, 62.22; H, 3.88; N, 15.80; Cl, 10.13.

Example 252: 8-(4-Dimethvlamino-pyrimidin-2-vlamino)-1,5-dihvdro-n .21diazepinof4.5.6-cdiindol- 20 6-one ci AA,

(CH3)2NH, EtOH

Et3N, 23 °C, 55%

252(a)

Title Compound ofExample 2 -->.

K2CO3, DMF, 100 °C

TT 'N" "N

I H H 19% Çtep 1.2-Chloro-4-Dimethylaminopyrimidine 252(a)

To a solution of 2,4-dichloropyridine (2.24 g, 15 mmol) in éthanol (45 mL) was addedtriethylamine (2.1 mL, 15 mmol) followed by dimethylamine (7.5 mL, 1.0 M in THF). The resulting 25 013017 254 mixture was stirred at 23 °C for 2 h. Extractive work-up from ethyl acetate and saturatedaqueous NaHCO3 afforded the cmde product, which was purified by silica gel chromatography,eluting with 30 % ethyl acetate\hexane to furnish Intermediate 252(a) (1.4 g, 8.2 mmol) in 55%yield. 5 Step 2. Préparation of Title Compound: 8-(4-Dimethylamino-pyrimidin-2-ylamino)-1,5-dihydro-[1,2]diazepino[4,5,6Jindoi-6-one A mixture of Intermediate 252(a) (212 mg, 1.35 mmol), the title compound of Example 2(freebase) (320 mg, 1.6 mmol), K2CO3 (560 mg, 4.05 mmol) in W,W-dimethylformamide (5 mL)was heated at 100 °C for 4 h. Extractive work-up from ethyl acetate and saturated aqueous 10 NaHCO3 afforded the crude product, which was triturated with methanol. The mixture wascollected by filtration and washed with methanol to give the title compound as a yellow solid (83mg, 0.26 mmol) in 19 % yield. 1H NMR (d6-DMSO): □ 11.63 (s, 1H), 10.12 (s, 1 H), 9.15 (s, 1 H), 8.15 (d, 1H, J = 1.8 Hz), 7.94 (d,1H, J = 6.1 Hz), 7.92 (d, 1H, J = 1.6 Hz), 7.46 (d, 1H, J = 2.5 Hz), 7.43 (s, 1H), 6.11 (d, 1H, J = 6.1 15 Hz), 3.08 (s, 6H). LCMS: (M+H+) 322.3.

Example 253: (1R.2R)-2-Phenvl-cvclopropanecarboxvlic acid [2-f1H-imidazol-2-vh-6-oxo-5.6- dihvdro-1H-f1.21diazepinof4.5.6-cdlindol-8-vl1-amide

Intermediate 230(a)of Example 230

NH4OH, THF, 23 °C,24%

acid tert-butyl ester 253(a)

To a solution of Intermediate 230(a) of Example 230 (274 mg , 0.835 mmol) in tetrahydrofuran (5mL) and éthanol (1 mL) was added 15N ammonium hydroxide (0.5 mL) followed by 40% glycol in 013017 255 water (0.5 mL). The resulting mixture was stirred at 23 °C overnight. Extractive work-up fromethyl acetate and saturated aqueous NaHCO3 afforded the crude product, which was purified bysilica gel chromatography, eluting with 50 % ethyl acetate\hexane to furnish the intermediate253(a) (75 mg, 0.2 mmol) in 24% yield.

Step 2. Préparation of Title Compound; 2-Phenyl-cyclopropanecarboxylic acid [2-(1H-imidazol-2-yl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6]indol-8-yl]-amide; compound with 10 15 20 acetic acid.

Deprotection of Intermediate 253(a) (41 mg, 0.11 mmol) in CH2CI2 (2 mL) using 4M HCl indioxane (2 mL) was carried out analogously to Example 91 . After concentration, the residue wasdissolved in Λ/,/V-dimethylformamide (5 mL). (1R, 2R)-2-Phenyl-cyclopropanecarbbxylic acid (35.6mg, 0.22 mmol), triethylamine (0.046 mL, 0.33 mmol), and 0-(7-azabenzotriazol-1-yl)-/V,A/,/V’,/V-tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) were sequentially added. After 12h, the mixture was concentrated. The crude product was purified by préparative HPLC in amanner analogous to Example 146, Step 2, to give the title compound as a pale yellow powder (7mg, 0.017 mmol) in 15% yield. 1H NMR (de-DMSO): 12.27 (s, 1H), 11.79 (s, 1H), 10.25 (s, 1H), 10.21 (s, 1H), 7.93 (d, 1H, J = 1.7Hz), 7.90 (s, 1H), 7.45 (d, 1H, J = 1.7 Hz), 7.20 (s, 1H), 7.13-6.99 (m, 5H), 2.19 (m, 1H), 1.89 (m,1H), 1.31 (m, 1H), 1.18 (m, 1H). LCMS: (M+H+) 409.

Example 254: (1R,2R)-2-Phenvl-cvclopropanecarboxylic acid f2-cvano-6-oxo-5,6-dihvdro-1 A7- H.2)diazepinoi4,5,6-ccHindol-8-vl)-amide, compound with HOAc sait.

Stepl: 2-Phenyl-cyclopropanecarboxyIic acid (2-formyl-6-oxo-5,6-dihydro-1W- [1,2ldiazepino[4,5,6-cdJindol-8-yl)-amide 254(a) 25 Préparation of starting material, 2-phenyl-cyclopropanecarboxylic acid (6-oxo-2-vinyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc/]indol-8-yl)-amide, was carried out by deprotecting the title compoundfrom Example 164 in a manner analogous to Example 91 and then coupling to the amide in a 013017 256 manner analogous to Example 61. The 2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-vinyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc(Jindol-8-yl)-amide (542 mg, 1.46 mmol) was then treated withK3Fe(CN)6 (483 mg, 1.46 mmol) and NalO4 (1.25 g, 5.84 mmol) in tetrahydrofuran (5 mL) andwater (2 mL) analogously to Example 230, step 1 . Extractive work-up from ethyi acetate and 5 saturated aqueous NaHCO3 afforded the crude product, which was purified by silica gelchromatography, eluting with 50% ethyi acetate\hexane to furnish intermediate 254(a) (384 mg,1.17 mmol) in 71 % yield.

Step 2. Title compound: 2-Phenyl-cyclopropanecarboxylic acid (2-cyano-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6]indol-8-yl)-amide, compound with HOAc sait. 10 A mixture of Intermediate 254(a) (103 mg, 0.276 mmol), NH2OH HCI (38 mg, 0.55 mmol) andtriethylamine (0.15 mL, 1.1 mmol) in éthanol (2 mL) was stirred at 23 °Ç for 1 h. Extractive work-up from ethyi acetate and saturated aqueous NaHCO3 afforded the crude product, which wasdissolved in tetrahydrofuran (2 mL) and triethylamine (0.077 mL, 0.55 mmol). Trifluoroaceticanhydride (0.046 mL, 0.33 mL) was then added dropwise. The resulting mixture was stirred 15 ovemight. Extractive work-up from ethyi acetate and saturated aqueous NaHCO3 afforded thecrude product, which was purified by préparative HPLC in a manner analogous to Example 146,Step 2, to give title compound (5 mg, 0.014 mmol) in 5% yield. 1H NMR (ds-DMSO): 9.05 (s, 1H), 8.74 (s, 1 H), 8.09 (s, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.24-7.12(m, 5H), 2.19 (m, 1H), 1.89 (m, 1H), 1.52 (m, 1H), 1.11 (m, 1H). 20 LCMS: (M+H+) 369.1.

Other compounds that were prepared from the appropriate starting materials include the following:Example 255: (2R-2-Amino-/\/-f6-oxo-5,6-dihvdro-1H41.21diazepinof4.5.6-cdlindol-8-vn-4-phenvl- butvramide fhvdrochloric sait):

25 Example 256: f2R)-2-Amino-2-indan-2-vl-A/-f2-( 1 -methyl-1 H-pvrazol-4-vl)-6-oxo-5,6-dihvdro-1 H- 11.21diazepinol4.5.6-cdlindol-8-vll-acetamide (hvdrochloric sait):

Example 257:_(2R)-2-Amino-A/-f2-f 1 -methyl-1 H-pvrazol-4-vl)-6-oxo-5,6-dihydro-1 H- f1.21diazepinof4.5,6-cdlindol-8-vll-4-phenvl-butyramide(hvdrochloricsalt): 013017 257

Example 258: (2R)-2-Amino-2-indan-2-vl-A/-(6-oxo-5,6-dihvdro-1H-f1 .21diazepinof4.5,6-cdlindol-8- vl)-acetamide fhvdrochloric sait);

Example 259: (2R)-2-Amino-3-ethvi-heptanoic acid f2-f1-methvl-1H-pvrazoM-vh-6-oxo-5.6- dihydro-IH-fl .21diazepinof4.5,6-cd}indol-8-vn-amide (hvdrochloric sait):

10 Example 260: (2R)-2-Amino-/V-(2-bromo-6-oxo-5,6-dihvdro-1 H-11,21diazepino[4,5,6-ccflindol-8-vl)- 4-phenvl-butvramide fhvdrochloric sait);

Example 261 : f2R1-2-Amino-2-indan-2-vl-A/-f2-(6-methvl-pvridin-3-vh-6-oxo-5.6-dihvdro-1 H- 15 ri,21dia2epinof4.5.6-cdlindol-8-vll-acetamide (hvdrochloric sait);

Example 262: (2R)-2-Amlno-ZV-(2-chloro-6-oxo-S.6-dihvdro-i /-/-ri .21dlazeplnor4.5,6-cdlindoi-8-vh- 4-phenvl-butvramide (hvdrochloric sait); 013017 258

Example 263: (1S,2R)-1-Amino-2-phenvl-cyclopropanecarboxvlic acid i2-(1-methvl-1rt-pyrazol-4- vl)-6-oxo-5,6-dihvdro-1H-f1.21diazepinoi4,5,6-cdlindol-8-yl1-amide fhvdrochloric saltk

Example 264: f2R)-2-Amino-3-f4-fluoro-phenoxv)-A/-r2-f 1-methvl-1 rt-pyrazol-4-vl)-6-oxo-5,6- dihvdro-1H-H .21diazepinoi4.5.6-ccHindol-8-vn-propionamide fhvdrochloric sait):

10

Example_265:_f2R)-2-Amino-/V-l2-(1-methvl-1H-pyrazol-4-vh-6-oxo-5.6-dihydro-1/-f- Γ1.21diazepinof4,5.6-cc/lindol-8-vl]-3-phenoxy-propionamide fhvdrochioric sait):

15 Example 266: f2R)-2-Amino-/V-(2-chloro-6-oxo-5J6-dihvdro-1 /7-Γ1.21diazepinof4.5.6-cdlindol-8-vh- 2-indan-2-vl-acetamide (hvdrochloric sait):

Example_267:_f2R)-2-Amino-A/-f2-(1-methyl-1 H-imidazol~4-vl)-6-oxo-5.6-dihydro-1 H- [1.21diazepinof4,5.6-conindol-8-vn-4-phenyl-butvramide (hvdrochloric sait): 013017 259

Example 268: f2R)-2-Amino-A/-f2-f6-methvl-Pvridin-3-vh-6-oxo-5.6-dihvdro-1H- f1.2ldiazepinof4.5,6-ccflindol-8-vH-4-phenyl-butvramide fhydrochloric sait);

Example 269:

(2R)-2-Amino-<V-f2-(3-methvl-isoxazol-5-vl)-6-oxo-5,6-dihvdro-1H- f 1,21diazepinof4.5.6-cdlindol-8-vn-4-phenvl-butvrarnide (hvdrochloric sait):

10

Example 270: (2R)-2-Amino-2-indan-2-vl-/V-[2-(3-methyl-isoxazol-5-vh-6-oxo-5,6-dihvdro-1 H- Î1.2]diazepinof4.5.6-cdlindol-8-vl1-acetamide (hvdrochloric sait):

Example_271:_2-Benzvlamino-JV-i2-( 1 -methvl-1 H-pyrazol-4-vl)-6-oxo-5.6-dihvdro-1 H- f1.21diazepinof4.5.6-cdlindol-8-vl1-acetamide (hvdrochloric sait):

HN-N HCLHN^l

Example 27?· (?R1-2-Amino-2-cvclohexvl-/\/-f2-( 1 -methvl-1 H-imidazol-4-vD-6-oxo-5.6-dihvdro-1 H-Π ,21diazepino[4.5,6-cdlindol-8-vn-acetamide (hvdrochloric sait); 15 013017

Example 273: (2R)-2-Amino-2-indan-2-vl-A/-r2-(1-methyl-1/-/-imidazol-4-vh-6-oxo-5.6-dihvdro-1/-/- 11.2ldiazepinof4,5,6-cdlindol-8-vll-acetamide (hvdrochloric sait):

Example 274: (2R)-2-Amino-2-(4-fluoro-phenvl)-/V-f2-(1-methvl-1H-pvrazol-4-vl')-6-oxo-5.6- dihvdro-1H-ft ,21diazepinof4,5.6-cdlindol-8-vl1-acetamide (hvdrochloric sait);

10

Example 275: In Vitro Combination Studies

Cancer cells can be incubated with an antineoplastic agent either alone or in combination with a CHK-1 inhibitor of formula 1. Cell growth data from a combination study (antineoplasticagent together with a fixed concentration of test compound) can be compared to corresponding 15 data obtained from a single agent study (antineoplastic agent without test compound). Theconcentration of antineoplastic agent causing 50% cell growth inhibition (ICS0) can be determinedfor both single agent treatment and combination treatment. IC5o values can be calculated usingthe linear portion of a semi-log plot of antineoplastic agent concentration versus percent cellgrowth inhibition. The ratio between the IC50 of the antineoplastic agent alone and the IC5D of the 20 antineoplastic agent in combination with test compound représente the Potentiation Factor 50(PF50). The PF50 can be useo to measure the effectiveness of the combination treatment.Combination treatment with an antineoplastic agent and test compounds of formula I can providePF50 values ranging from 2 to 8 in cancer cells. 01301/ 261

Cancer cell viability and prolifération cari be evaluated using a tétrazolium sait réductionassay (MTT assay). In viable cells, this colorimétrie assay can measure mitochondrial réduction ofa tétrazolium component into an insoluble formazan product. Conversely, this assay can be usedto détermine whether or not mitochondrial function is impaired, for instance, by the metabolic 5 events leading to apoptosis or necrosis. Cancer cell lines can be grown in 96-well plates and canbe plated in the appropriate medium at a volume of 100 ul/well. Plates can be incubated for fourhours before the addition of test compounds. On the bottom part of the 96 well plate, cells can betreated with increasing concentrations of antineoplastic agent On the top part of the plate, cellscan be treated with increasing concentrations of antineoplastic agent combined with a fixed 10 concentration of test compound. Cells can be incubated at 37°C (5% CO2) for four to six days(depending on cell type). At the end of the incubation, the tétrazolium component can be added toa final concentration of 0.2 mg/ml, and cells can be incubated for 4 hours at 37°C. Aftercentrifugation of the plates and removal of medium, the absorbance of the formazan (solubilizedin dimethylsulfoxide) can be measured at 540nm. 15 Antineoplastic agents can include cisplatin, hydroxyurea, gemcitibine, carboplatin, 7-ethyl- 10-hydroxycamptothecin (SN-38), and cytosine β-D-arabinoside.

Cancer cells can refer to the following:

Cell Line Cancer Tvoe CA-46 (human) lymphoma HT-29 (human) colon Colo205 (human) colon MV522 (human) lung SW620 (human) colon L1210 (murine) leukemia PANC-1 (human) pancréas BXPC-3 (human) pancréas MCF-7 (human) breast 013017 262 HCT116 (human) colon H23 (human) iung

Example 276: In Vivo Tumor Models

To assess the ability of CHK-1 inhibitors of formula I to augment réduction in tumorvolume in combination with gemcitibine in mice, xenograft tumor models using HT-29, MV522 or 5 Colo205 tumor cell lines can be established.

Mice can be randomized (12 mice/group) into treatment groups and used when tumorsreach a volume of 150-200 mm3. Mice can undergo a course of intraperitoneal (i.p) injectionsconsisting of vehicle alone, gemcitibine alone or gemcitibine in combination with the testcompound of formula I. Tumor volumes can be measured at times ranging from 2 to 25 days. 10 Control can consist of i.p. injection of vehicle at appropriate intervals. Parallel contrai can consistof i.p. injection of gemcitibine alone at 15 mg/kg to 240 mg/kg at appropriate intervals. Treatmentcan consist of i.p. injection of gemcitibine (5 mg/kg to 240 mg/kg) at appropriate intervals incombination with i.p. injection of the test compound of formula I (1 mg/kg to 100 mg/kg) atappropriate intervals. At the end of the study, tumor volume (mm3) can be measured. An 15 enhancement in the delay of tumor growth can be observed in the mice treated with gemcitibine in combination with the test compound of formula I versus gemcitibine treatment alone.

While the invention has been illustrated by référencé to spécifie and preferredembodiments, those skilled in the art will recognize that variations and modifications may be madethrough routine expérimentation and practice of the invention. Thus, the invention is intended not 20 to be limited by the foregoing description, but to be defined by the appended daims and theiréquivalents.

Claims

013017 263 We Claim:

1 -Acetyl-W-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)piperidine-4-carboxamide; 5 3-(2-Methylphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/|indol-8- yl)propanamide; (2S)-2-Amino-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-phenyl-butyramide compound with trifluoro-acetic acid; (2R)-2-Amino-2-cyclohexyl-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-10 cd]indol-8-yl)ethanamide trifluoroacetate; ( 1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cdJindol-8-yl)-amide;

1. A compound of the formula:

wherein: X is =0 or =S; A is =CR1-or =N-; The group -Y-Z- has the formula -O-CH2- or -N=CH-; R1 is: (a) (CrC8)alkyl; (b) -C(=O)-R6; (c) -C(=O)-NR6R7; or (d) R35, or R36, (C2-C8)alkenyl, or (C2-C8)alkynyl {wherein each of said (C2-C8)alkenyl or (C2-C8)alkynyl is unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of F, Cl, OH, -NH2, R40, and R42}; R2is (a) H, OH, or (CrC8)alkyl; (b) -C(=O)-R8; (c) -(C=S)-R9 or -(C=S)-NR10R11; or (d) R38orR39; R3is (a) (Ci-C8)alkyl; (b) -C(=O)-R12; (c) -C(=O)-NR13R14; (d) -NR15-C(=O)-R16; (e) -NR17-SO2R18; (f) -NR1s-SOn-NR20R21 {wherein n is 1 or 2}; (g) -NR22-(C=S)-R23 or-NR22-(C=S)-NR23R24; (h) R36, (C2-C8)alkenyl, or (C2-C8)alkynyl {wherein each of said R3 (C2-C8)alkenyl or (C2-C8)alkynyl is unsubstituted or substituted with one to four substituents independently selected 013017 264 from the group consisting of -(C=O)-O-(C1-C8)alkyl, -O-(C=O)-(CrC8)alkyl, -(C=O)-(C1-C8)alkyl,R40, R41, and R42}; (i) R37, -NH2, -NH((C2-C8)alkenyl), -NH((C2-C8)alkynyl), -N((O1-C6)alkyl)((C2-C8)alkenyl), or-N((Ci-C8)alkyl)((C2-C8)alkynyl) {wherein each of said R26 (C2-C8)alkenyl or (C2-C8)alkynyl isunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of R40, R41, and R42}; or ü) R38; R4 is selected from the group consisting of H, F, Br, Cl, and (CrCaJalkyl; R5 is selected from the group consisting of H, (Ci-C8)alkyl, (Ci-C8)alkyl-O-, and R36; Each R6 and R7 are independently selected from the group consisting of H, (C1-C8)alkyl, and R36; R8 is selected from the group consisting of (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,-NH2, R36, and R37; Each of R9, R10 and R11 are independently selected from the group consisting of H,(Cn-C8)aHcyl, and R36; R12 is selected from the group consisting of H, OH, (CrC8)alkyl, (^-Celalkyl-O-, and R36; R13isHor(C,-Cs)alkyl; R14 is selected from the group consisting of H, (CrC8)alkyl, -CH2-(C=O)-O-(C1-C8)alkyl, and R36; R15 is H or (CrC8)alkyl; R16 is selected from the group consisting of H, (CrCa)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,-NH2, R36, and R37; wherein each of said R15 and R16 (C2-C8)alkenyl or (C2-C8)alkynyl is unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of R40,R41, and R42; R17 is selected from the group consisting of H, (Ci-CB)alkyl, and R36; Rieis(Ci-C8)alkyl or R36; R19, R20, and R21 are independently selected from the group consisting of H, (Ci-C8)alkyl, and R36; R22, R23 and R24 are independently selected from the group consisting of H, (CrC^alkyl, and R36; R25 is H or (CrC^alkyl; R26 is selected from the group consisting of -C(=O)-O-C(CH3)3, (CrC^alkyl,(C3-Ci0)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, and (CrC^heteroaryl; or R25 and R26 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; 013017 265 R27 is selected from the group consisting of (C,-C8)alkyl, (C3-C1D)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (CrC10)heteroaryJ; R28 is selected from the group consisting of (C-i-Ce)alkyl, (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-Cio)aryl, and (C,-C10)heteroaryl; R29 is H or (CrCsJalkyl; R30 is (CrCeJalkyl, (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-Ci0)aryl, or(Ci-C10)heteroaryl; or R29 and R30 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; R31 is H or (CrCsIalkyl; R32 is independently selected from the group consisting of (^-Cejalkyl, (C3-C10)cycloalkyl,(CrC 10)heterocyclyl, (C6-C10)aryl, and (Ci-C10)heteroaryl; or R31 and R32 may optionally be taken together with the nitrogen to which they areattached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; R33 is (C1-C8)alkyl, (C3-Ci0)cycloalkyl, (C2-C10)heterocyclyl, (C6-Cio)aryl, or (C^CtoJheteroaryl; R34 is (C^-Cgjalkyl, (C3-Ci0)cycloalkyl, (C2-C10)heterocyclyl, (C6-Ci0)aryl, or (C,-C10)heteroaryl; Each R35 is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH,NO2, -NH2, -NH-C(=O)-O-C(CH3)3i and CF3; Each R38 is independently selected from the group consisting of (C3-Ci0)cycloalkyl,(C2-C i0)heterocyclyl, <C6-C10)aryl, and (Ci-CiO)heteroaryl; Each R37 is independently selected from the group consisting of: (c) -NR25R26; and (d) R27-O-; R38 is R28-SOn-; wherein n is 0,1, or 2 when -SOn- is bonded to R28 via an R28 carbonatom, or wherein n is 1 or 2 when -SOn- is bonded to R28 via an R28 ring nitrogen atom; R39 is R2SR30N-SO„-; wherein n is 1 or 2; wherein each of said (Ci-CB)alkyl, wherever it occurs in any of said R1(a)-(d), R2(a)-(d),R3(a)-(j), R4, R37, R38, or R39, is unsubstituted or substituted with one to four substituentsindependently selected from the group consisting of (C2-CB)alkenyl, R40, R41, and R42; wherein each of said (C3-C10)cycloalkyl, (C2-Cio)heterocyclyl, (C6-Ci0)aryl, or(Ci-Cio)heteroaryl, wherever it occurs in said R36, R37, R38, or R39, is independently unsubstitutedor substituted with one to four substituents independently selected from R40; R40 is selected from the group consisting of (Ci-CsJalkyl, R41, R42, and R43; 013017 266 Each R41 is independently selected from the group consisting of F, Cl, Br, I, CN, OH,NO2, -NH2i -NH-C(=O)-O-C(CH3)3, COOH, -C^OXCrCelalkyl, -C(=0)-O-(C1-C8)alkyl,-NH-SO2-(Ci-C8)alkyl, -NH-S02*(Cg-Cio)aryi, and CF3; Each R42 is independently selected from the group consisting of (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (CrCi0)heteroaryl; Each R43 is independently selected from the group consisting of: (c) -NR31R32; (d) R33-O-; and (c) R34-SOn-; wherein n is 0,1, or 2 when -SO„- is bonded to R34 via an R34 carbon atom,or wherein n is 1 or 2 when -SOn- is bonded to R34 via an R34 ring nitrogen atom; wherein each of said (Ci-Ce)alkyl, wherever it occurs in any of R40 is independentlyunsubstituted or substituted with one to four substituents independently selected from the groupconsisting of R44 and R45; wherein each of said (C3-C10)cycloalkyl, (C2-C10)heterocyclyl, (C6-C10)aryl, or(CrC 10)heteroaryl, wherever it occurs in any of said R42 or R43, is independently unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of R47selected from the group consisting of (C,-C8)alkyl, R44, and R45; Each R44 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NO2,-NH2, -CF3i -C(=NH)-NH2i -C(=NH)-NH-OH, -C(=NH)-NH-O-(C1-C8)alkyl, -(C=O)-O-(CrC8)alkyl,-O-{C=O)-(C,-C8)alkyl, -(C=O)-(CrC8)alkyl, -(C=O)-NHZ, -(C=O)-NH(C1-C8)alkyl,-(C=O)-N<[(C1-C8)alkyl]2, -NH-(C=O)-(CrC8)alkyl, R37, and R38; Each R45 is independently selected from the group consisting of (C3-C10)cycloalkyl,(C2-C10)heterocyclyl, (C6-C10)aryl, and (CrCi0)heteroaryl; wherein each of said (C1-C8)alkyl wherever it occurs in any of said R44 or R45 isindependently unsubstituted or substituted with one to four substituents independently selectedfrom the group consisting of R46 and R47; wherein each of said (C3-Ci0)cycloalkyl, (C2-C10)heterocyclyi, (C6-Cio)aryl, or(CrC1o)heteroaryl, wherever it occurs in any of said R43 or R44 is independently unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of(CrC8)alkyl, R46 and R47; Each R46 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NO2,-C(=NH)-NH2, -C(=NH)-NH-OH, -C(=NH)-NH-O-(Ci-C8)alkyl, -(C=O)-O-(CrC8)alkyl,-O-(C=O)-(C1-Ce)alkyl, -(C=O)-(CrC8)alkyl, -(C=O)-NH2, -(C=O)-NH(C1-C8)alkyl,-(C=O)-N<[(C1-c8)aikyij2, -NH-(c=ü)-(C,-c8)aikyi, -C(=nh)-nh2, -C(=nh)-nh-oh, -C(=NH)-NH-O-(C1-C8)alkyl, -(C=O)-O-(CrCs)alkyl, -O-(C=O)-(C1-C8)alkyl, -(C=O)-(CrCB)alkyl,-(C=O)-NH2, -(C=O)-NH(C1-C8)alkyl, -(C=O)-N>[(C1-C8)alkyl]2, -NH-(C=O)-(C1-CB)alkyl, R37, andR38; and 013017 267 Each R4' is independently selected from the group consisting of (C3-Ci0)cycloalkyl;(C2-C1D)heterocyclyl, (C6-C10)aryl, and (Ci-C10)heteroaryl; or a pharmaceutically acceptable sait thereof.

2-Fiuoro-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2ldiazepino[4,5,6-cd]indol-8-yl)-3- trifluoromethyl-benzamide; A/-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-trifluoromethyl- benzamide; /V-(6-Oxo42-phenyl4},6<iihydro-1 W-il^jdiazepinG^.S.e-ccOincol-e-yl^-thien-^-yibLitanamide; /V-[2-{3-Dimethylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol- 8-yl]-2-fluoro-3-trifluoromethyl-benzamide; (2R)-2-Amino-2-cyclohexyl-W-(6-oxo-2-phenyl-5,6-dihydro-1H41,2]diazepino[4l5,6- cdjindol-8-yl)-acetamide(hydrochloride); (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ctf|indoI-8-yl)-amide; (lR,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyî)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; (2R)-2-Amino-2-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-ô,6-dihydro-1 H- [1.2] diazepino[4,5,ô-cd]indol-8-yl)ethanamide hydrochioride; (1,2-frans)-2-(4-Hydroxy-phenyl)-cyciopropanecarboxylic acid (6-oxo-2-phenyi-5,6-dihydro-1-[1,2Jdiazepino[4,5,6]indol-8-yl)-amide; and (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethy!-6-oxo-5,6-dihydro-1 H- [1.2] diazepino{4,5,6-cdJindol-8-yl)-amide; or a pharmaceutically acceptable sait or solvaté thereof.

2-Fluoro-A/-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-3-triflucromethyl-benzamide; /\46-Oxo-2-phenyl-5,6-dihydro-1/7-[1,2]diazepino[4,5,6-cd)Îndol-8-yl)-4-thien-2- ylbutanamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2Jdiazepino[4,5,6-cdIindol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylaminomethyl-phenyl)-6-oxo- 5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cc(]indol-8-yl]-amide; Acetic acid 3-{6-oxo-8-[((1R, 2R)-2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccf|indol-2-yl}-benzyl ester; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-ccfIindol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepinoI4,5,6-cdJindol-8-yl)-acetamide; (1R,2R)-2-Phenyl-cyclopropanecarboxyiic acid (6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-c(flindol-8-yl)-amide; {1 R,2R)-2-Phenyl-cyclopropanecarboxyiic acid [2-(3-cyclobutylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd|indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1-ylmethyl-phenyl)- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; 2-lndan-2-yl-/V-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-ccOindol-8-yl)- acetamide; (1,2-frans)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide; (2R)-2-Amino-3-(4-hydroxyphenyl)-W-(6-oxo-2-phenyl-5,6-dihydro-1/-/- [1.2] diazepino[4,5,6-cd]indol-8-yl)propanamide; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid methyl ester; (1 R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cc/]indole-2-carboxylic acid methylamide; (iR,2R)-6-Oxo-8-[(2-phenyl-cyciopropanecarbonyl)-aminol-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid (2-hydroxy-ethyl)-amide; (1R,2R}-6-Oxo-8-[(2-phenyl-cyçlopropanecarbonyi)-amino]-5,6-dihydro-1H- [1,2]diazepino[4,5,6-cd]indole-2-carboxylic acid (2-hydroxy-ethyl)-amide; j-y / 273 (2-ethyl-6-oxo-5,6-dihydro-1H- (2-ethyl-6-oxo-5,6-dihydro-1 H- (2R)-2-Amino-2-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-c£/]indol-8-yl)ethanamide; (1,2-frans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxyiic acid (6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cc0indol-8-yl)-amide; (1,2-frans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1-[1,2ldiazepino[4,5,6]indol-8-yl)-amide; ( 1R ,2R)-2-Phenyl-cyclopropanecarboxylic acid [1.2] diazepino[4,5,6-cc(Iindol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1.2] diazepino[4,5,6-cc/lindoi-8-yl)-amide; 2-(3,4-Dihydroisoquinolin-2(1H)-yl)-W-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cc0indol-8-yl)acetamide; 2-(3,4-Dihydroisoquinolin-2(1 H)-yl)-A/-{6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cdJindol-8-yl)acetamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid f6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)- 5.6- dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1R,2R)-A/-(6-Oxo-2-pyridin-4-yi-5,6-dihydro-1H-[1,2]diazepino[4t5,6-cdJindol-8-yl)-2- phenylcyclopropanecarboxamide; (1R,2R)-A/-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1W-[1t2]diazepino[4,5,6-cc/3indol-8-yl)-2- phenylcyclopropanecarboxamide; ( 1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-prop-1 -ynyt)-6-oxo- 5.6- dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-propenyl)-6-oxo-5,6-dihydro-1 ,2]diazepino[4,5,6-c£/Iindol-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5)6-cdJindol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-/V-[2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1H- [I^JdiazepinotA.S.S-ccOindol-e-yO-acetamidede; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-hydroxymethyl-6-oxo-5,6-dihydro-1 H-[1,2-cc/|diazepino[4,5,6]indol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxyiic acid [6-oxo-2-(3-pyrrolidÎn-1-yl-prop-1 -yny 1)-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-( 1 H-imidazoi-2-yl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-ccf|indol-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-cyano-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; and 013017 274 (2R)-2-Amino-2-(4-hydroxyphenyl)-W-(6-oxo-2-phenyl-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cdJindol-8-yl)ethanamide hydrochloride; or a pharmaceutically acceptable slat or solvaté thereof.

2-Ethylsulfanyl-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cc/]indol-8-yl)-nicotinamide; 15 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; W-[2-(3-Dimethylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol- 8-yl]-2-fluoro-3-trifluoromethyl-benzamide;

2-Fiuoro-A/-(6-oxo-2-phenyl-5,6-dihydro-1/7-[1,2]drazepino[4,5,6-cd]indol-8-yl)-3- 30 trifluoromethyl-benzamide; W-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-2-trifluoromethyl-benzamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxyiic acid (6-oxo-2-phenyl-5,6-dihydro-1H- [1,2]diazepino[4,5,6-ccf]indol-8-yl)-amide; 35 2-(3-Chlorophenyl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-ccijindol-8- yl)acetamide; 013017 268 W-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd|indol-8-yl)-4-thien-2- yibutanamide;

2- Cyclohexyl-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide; W-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-phenyl-butyramide; 25 N-(6-Oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-3-phenyl- propionamide;

2. A compound according to claim 1 wherein R3 is -NR1S-C(=O)-R16; wherein R16 is5 (C3-C10)cycloalkyl unsubstituted or substituted with one or two substituents independently selected from the group consisting of (Ci-C8)alkyl, F, Cl, CN, OH, NH2, CF3, (C2-C10)heterocyclyl,(C6-Cio)aryl, and (C,-Ci0)heteroaryl; wherein said (C6-C10)aryl substituent is unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of(Ci-Cs)alkyl, F, Cl, Br, CN, OH, and CF3; and wherein said (C2-C10)heterocyclyl substituent is 10 unsubstituted or substituted with one or two substituents independently selected from the groupconsisting of (CrC8)alkyl, -(C=O)-(CrC8)alkyl, -(C=O)-O-(C5-C8)alkyl, -S-(Ci-C8)alkyl, F, Br, OH,and CF3.

3-Fluoro-2-methyl-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/lindol-8-yl)-benzamide;

3- Fluoro-2-methyl-/V-(6-oxo-2-phènyl-5)6-dihydro-1H-[1,2]diazepino[4,5,6-ccf]indQl-8-yl)-benzamide;

3. A compound according to claim 1 wherein Rz is H or (CrC^alkyl unsubstituted orsubstituted with one to four substituents independently selected from the group consisting of OH,

15 -NH2, (Ci-C8)alkyl-NH-, K^-CeJalkyl^N-, (C2-C10)heterocyclyl, and (CrC10)heteroaryI.

4. A compound according to claim 1 wherein X is =0.

5. A compound according to claim 1 wherein the group -Y-Z- has the formula-N=CH-,

6-Oxo-2-phenyl-W-[(1/?)-1-phenylethyl]-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cflf|indole-8- carboxamide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H- [1,2Jdiazepino[4,5,6-cd]indol-8-yl)-amide; (2R)-2-Hydroxy-W-(6-oxo-2-phenyl-5t6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2- phenylethanamide; (1,2-fra/Js)-2-Pyridin-2-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd|indol-8-yl)-amide (acetic acid sait); (1,2-frans)-2-(1H-lmidazol-4-yl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-amide (acetic acid sait); (2R)-Piperidine-2-carboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-amide (hydrochloric sait); (2R)-2-Amino-3-(4-hydroxyphenyl)-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2Jdiazepino[4,5,6-cd]indol-8-yl)propanamide hydrochloride; (1R,2R)-6-Oxo-8-[(2-phenyl-cyclopropanecarbonyI)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; (1,2-fra/?s)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 -[1,2]diazepino[4,5,6]indol-8-yl)-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; (1 R,2R)-/V-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenylcyclopropanecarboxamide; and (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1-(2-amino-ethyl)-2-chloro-6-oxo-5,6-dihydro-1/7-[1,2]diazepino[4,5,6-cd)indol-8-yl]-amide; or a pharmaceutically acceptable sait or solvaté thereof. 013017 275

6-Oxo-2-phenyl-W-(2-phenylcyclopropyl)-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindole-8-20 carboxamide; Λ/-[1 -(4-Fluorophenyl)ethyl]-6-oxo-2-phenyl-5,6-dihydro-1 /7-[1 ,2]diazepino[4,5,6-cc/]indole-8-carboxamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylaminomethyl-phenyl)-6-oxo- 5,6-dihydro-1 H-[î ,2]diazepino[4,5,6-ccf]indol-8-yl]-amide; 25 (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid |2-(3-dimethylaminomethyl-phenyl)-6-oxo- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide (hydrochloric sait); Acetic acid 3-{6-oxo-8-[((1R, 2R)-2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccQindol-2-yl}-benzyl ester; (1R, 2R)-2-Phenyl-cycl,opropanecarboxylic acid [2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-30 dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-ZV-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide (hydrochloric sait); A/-[1-(4-Hydroxypheny!)ethyl]-6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6- cdJindole-8-carboxamide; 35 2,3-Difluoro-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yI)- benzamide; 013017 269 (1R,2R)-2-Phenyi-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1H- [1,2]diazepino[4,5,6-cd]indol-8-yl)-amÎde; W^-FluorobenzyO-e-oxo^-phenyl-S.S-dihydro-IH-fl^Jdiazepino^.S.e-cdlindole-O- carboxamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-cyctobutylaminomethyl-phenyl)-6-oxo-5,6-dihydro-1 H-[1,2ldiazepino[4,5,6-ccf]indol-8-yl]-amide(hydrochloric sait); (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1-ylmethyl-phenyl)- 5,6-dihydro-1 W-[1,2]diazepino[4,5,6-c£flindol-8-yl]-amide(hydrochloric sait); W-(6-Oxo-2-phenyl-5,6-dibydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-(1,2-irans)-2-[6-(trifluoromethyl)pyridin-3-yl]cyclopropanecarboxamide trifluoroacetate; (2R)-2-AminoW-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenyl-acetamide (hydrochloric sait); (2R)-2-Amino-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-3- 1 phenyl-propionamide(hydrochloric sait); (3E)-4-Phenyl-but-3-enoic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino(4,5,6-cdJindol-8-yl)-amide; 2-lndan-2-yl-/V-(6-oxo-2-phenyl-5,6-dihydro-1/7-[1,2]diazepino[4,5,6-cc(jindol-8-yl)-acetamide; (1,2-frans)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-c<flindol-8-yl)-amide; (1,2-ira/îs)-2-Pyridin-3-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ccQindol-8-yl)-amide (hydrochloric sait); (1,2-frans)-2-(3-Methoxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6- dihydro-1 W-[1,2]diazepino[4,5,6-cc/]indol-8-yl)-amide; 2-lndan-2-yl-(6-oxo-5,6-dihydro-1-[1,2]diazepino[4,5,6-cti]indol-8-yl)-acetamide;(2R)-2-Hydroxy-A/-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-2- phenylethanamide; (1,2-frans)-2-Pyridin-2-yl-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1/7- [1.2] diazepinoI4,5,6-ccf|indol-8-yl)-amide acetic acid; (1,2-frans)-2-(1 H-lmidazol-4-yl)-cyclopropanecarboxyIic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdlindol-8-yl)-amide acetic acid; (2R)-Piperidine-2-carboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide (hydrochloric sait); (2S)- 2-Amino-3-cyano-W-(6-oxo-2-pheny!-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-propionamide acetic acid; (2R)-2-amino-3-(4-hydroxyphenyl)-W-(6-oxo-2-phenyl-5I6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indo1-8-yl)propanamide (hydrochloric sait); 013017 270 (1R,2R)- 6Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd|indole-2-carboxylic acid methyl ester; (2R)-3-(4-Hydroxÿphenyl)-2-(methylamino)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd]indol-8-yl)propanamide (hydrochloric sait); (2R)-2-Amino-3-(4-fluorophenyl)-/\/-(6-oxo-2-phenyl-5l6-dihydro-1/-/-[1,2]diazepino[4,5,6-cd]indol-8-yl)propanamide (hydrochloric sait); (1 R,2R)- 6-Oxo-8-I(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,5-ccflindole-2-carboxylic acid methylamide; (1 R,2R)- 6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-amino]-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-ccïjindole-2-carboxylic acid (2-hydroxy-ethyl)-amide; (1 R,2R)- 6-Oxo-8-[(2-phenyl-cyclopropanecarbonyl)-annino3-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cc/]indole-2-carboxylic acid (2-dimethylamino-ethyl)-amide; (2R)-2-Amino-2-(4-hydroxyphenyl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1H- [1.2] diazepino[4,5,6-ctflindol-8-yI)ethanamide (hydrochloric sait); ( 1,2-trans)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 - [1.2] diazepino[4,5,6]indol-8-yl)-amide; (1,2-ira/?s)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-2-phenyl-5,6-dihydro-1 -[1,2]diazepino[4,5,6]indol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-ethyl-6-oxo-5,6-dihydro-1W- [1.2] diazepino[4,5,6-cd|indol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-chloro-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cc/|indol-8-yl)-amide; (1,2-irans)-2-(3-Bromo-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cdJindol-8-yl)-amide; (1,2-fra/7s)-2-(3-Hydroxy-phenyl)-cyclopropanecarboxylic acid (6-oxo-5,6-dihydro-1- [1.2] diazepinoI4,5,6]indol-8-yl)-amide; 2-(3,4-Dihydroisoquinolin-2( 1 H)-yl)-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indol-8-yI)acetamide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid (2-bromo-6-oxo-5,6-dihydro-1tf- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(1,2,3,6-tetrahydro-pyridin-4-yl)- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdJindol-8-yl]-amide (hydrochloric sait); (1R,2R)-W-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1H-[1,2]diazepÎno[4,5,6-cdJindol-8-yl)-2- phenylcyclopropanecarboxamide; A/-(6-Oxo-2-pyridin-4-yl-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cdJindol-8-yl)-(1,2-fraos)-2- pyridin-3-ylcyclopropanecarboxamide; 013017 271. A/-(6-Oxo-2-pyrid in-3-y!-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-( 1,2-trans)-2-pyridin-3-ylcyclopropanecarboxamide; ( 1 R,2R)-W-(6-Oxo-2-pyridin-3-yl-5,6-dihydro-1 H-[î ,2]diazepino[4,5,6-cd]indol-8-yl)-2-phenylcyclopropanecarboxamide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-prop-1-ynyl)-6-oxo-S.e-dihydro-IH-fl^jdiazepino^.S.e-ccOindol-e-ylJ-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-propyl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/lindol-8-yl]-amide; (1R,2R)- 2-Phenyl-cyclopropanecarboxylic acid [2-(3-dimethylamino-propenyl)-6-oxo-5,6-dihydro-1 W-[1,2]diazepino[4,5,6-cc()indol-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-methylamino-prop-1-ynyI)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cdJindol-8-yl]-amide (hydrochloric sait); (1,2-frans)-2-Pyridin-3-yl-cyclopropanecarboxylic acid [2-(3-rnethylarnino-prop-1-ynyl)-6-oxo-5,6-dihydro-1 H-[î ^Jdiazepino^.S.e-cdlÎndol-e-yll-amide (dihydrochloric sait); (2R)-2-Amino-2-cyclohexyl-W-[2-(3-methylamino-prop-1-ynyl)-6-oxo-5,6-dihydro-1H- [1.2] diazepino[4,5,6-cd)indol-8-yl]-acetamide (dihydrochloric sait); (1,2-trans)-/V-[1-(2-Hydroxyethyl)-6-oxo-5,6-dihydro-1/-/-[1,2]diazepino[4,5,6-cc/]indol-8-yl]- 2-phenylcyclopropanecarboxamide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-dimethylaminomethyl-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1-(2-amino-ethyl)-6-oxo-5,6-dihydro-1/7- [1.2] diazepino[4,5,6-cd]indol-8-ylJ-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-morpholin-4-yl-prop-1-ynyl)-6-oxo- 5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [6-oxo-2-(3-pyrrolidin-1-yl-prop-1 -ynyl)-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]Îndol-8-yl]-amide; and (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid [1 -(2-amino-ethyl)-2-chloro-6-oxo-5,6- dihydro-1W-[1,2]diazepino[4,5,6-ccf|indol-8-yl]-amide; (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(1W-imidazol-2-yl)-6-oxo-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cc/]indol-8-yl]-amide; (1 R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-cyano-6-oxo-5,6-dihydro-1 H- [1.2] diazepino[4,5,6-cd]indol-8-yl)-amide; and (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(1/7-imidazol-2-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepinoI4,5,6-cdJindol-8-yl]-amide; or a pharmaceutically acceptable sait or solvaté thereof.

6. A compound according to claim 1 selected from the group consisting of: 20 W-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2Jdiazepino[4,5,6-cc0indol-8-yl)-2-phenyl-acetamide;

7. A compound according to claim 1 selected from the group consisting of: 013017 272

8. A compound according to claim 1 selected from the group consisting of:2-Fluoro-W-(6-oxo-2-phenyl-5,6-dihydro-1H-[1,2]diazepino[4,5l6-ci/]indol-8-yl)-3- trifluoromethyl-benzamide; /V-(6-Oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-4-thien-2-ylbutanamide; (1R, 2R)-2-Phenyl-cyclopropanecarboxylic acid [2-(3-hydroxymethyl-phenyl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-crf|indol-8-yl]-amide; (2R)-2-Amino-2-cyclohexyl-/V-(6-oxo-2-phenyl-5,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8-yl)-acetamide(hydrochloride);

9. A compound according to daim 1 selected from -the group consisting of:

10. A pharmaceutical composition comprising: (a) an effective amount of a CHK-1-inhibiting agent that is a compound according toclaim 1 ; or a pharmaceutically acceptable sait thereof; (b) an eiective amount of an anti-neoplastic agent or therapeutic radiation;and (c) a pharmaceutically acceptable carrier for said CHK-1 -inhibiting agent

11. A composition containing a compound according to claim 1 or a pharmaceuticallyacceptable sait or solvaté thereof and an antr-neoplastic agent as a combined préparation for thesimultaneous, separate or sequential use in treating a neoplasm.

12. Use of an anti-neoplastic agent or a therapeutic radiation having an anti-neoplastic effect in combination with a compound according to claim 1 cr a pharmaceuticallyacceptable sait or solvaté thereof, for treating a neoplasm in a mammal.

13. Use of a compound according to claim 1 or a pharmaceutically acceptable sait orsolvaté thereof, for the treatment of a condition which can be treated by the inhibition of proteinkinases in a mammal, including a human.